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Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

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Journal of Alzheimer’s Disease 32 (2012) 793–887 793
DOI 10.3233/JAD-2012-121186
IOS Press

Review

Cognitive Enhancers (Nootropics). Part 1:

Drugs Interacting with Receptors
Wolfgang Froestl∗ , Andreas Muhs and Andrea Pfeifer
AC Immune SA, EPFL, Lausanne, Switzerland

Accepted 1 July 2012

Abstract. Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer’s disease,
schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing,
applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and
psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed
in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To
classify the compounds, a concept is proposed assigning drugs to 19 categories according to their mechanism(s) of action, in
particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants,
metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with
amyloid-␤ and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g.,
peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.

Keywords: Alzheimer’s disease, cognitive enhancers, memantine, memory, nootropics, receptors

INTRODUCTION Cognitive enhancers (nootropics) are drugs to treat

As of May 28, 2012 there are 26,364 entries in
PubMed under the term cognitive enhancers, 26,429
entries under the term nootropic, and 217 entries
under the term cognition enhancers. Scifinder lists
5,029 references under the research topic nootropic,
504 references under the term cognitive enhancer, and
9,552 references for cognition enhancers. The Thom-
son Reuters Pharma database lists 1,081 drugs as
nootropic agents or cognition enhancers and gives zero
results under the term cognitive enhancer. The term
nootropics was coined by the father of piracetam Cor-
neliu Giurgea in 1972/1973 [1, 2]: NOOS = mind and
TROPEIN = toward.
∗ Correspondence to: Dr. Wolfgang Froestl, AC Immune SA,
EPFL Quartier de l’innovation building B, CH-1015 Lausanne,
Switzerland. Tel.: +41 21 693 91 21; Fax: +41 21 693 91 20; E-mail:
wolfgang.froestl@acimmune.com.
cognition deficits, which are most commonly found
in patients suffering from Alzheimer’s disease (AD),
schizophrenia, stroke, attention deficit hyperactiv-
ity disorder (ADHD), or aging. Cognition refers
to a capacity for information processing, applying
knowledge, and changing preferences. According to
Astrid Nehlig [3], it involves memory, attention,
executive functions, perception, language, and psy-
chomotor functions. Mark J. Millan and 24 eminent
researchers [4] presented an excellent overview on
cognitive dysfunction in psychiatric disorders in the
February 2012 issue of Nature Reviews Drug Discov-
ery and define cognition as “a suite of interrelated
conscious (and unconscious) mental activities, includ-
ing pre-attentional sensory gating, attention, learning
and memory, problem solving, planning, reasoning
and judgment, understanding, knowing and repre-
senting, creativity, intuition and insight, spontaneous
thought, introspection, as well as mental time travel,

ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved
794 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

self-awareness and meta cognition (thinking and 1.1. Acetylcholine Receptors

knowledge about cognition)”. 1.1.1. Muscarinic Acetylcholine Receptors
Since a first review in 1989 on “Families of Cogni- (mAChRs)
tion Enhancers” by Froestl and Maı̂tre [5], substantial 1.1.1.1. Orthosteric mACh M1 Recep-
progress has been made in the understanding of tor Agonists
the mechanism(s) of cognitive enhancers. Therefore, 1.1.1.2. Allosteric mACh M1 Receptor
we propose a new classification to assign cognition Agonists
enhancing drugs to 19 categories: 1.1.1.3. Vincamine-type Compounds
1.1.1.4. Muscarinic Acetylcholine M2
1. Drugs interacting with Receptors Receptor Antagonists
2. Drugs interacting with Enzymes 1.1.2. Nicotinic Acetylcholine Receptors
3. Drugs interacting with Cytokines 1.1.2.1. ␣4␤2 and ␣3␤4 Nicotinic
4. Drugs interacting with Gene Expression Acetylcholine Receptor Ago-
5. Drugs interacting with Heat Shock Proteins nists
6. Drugs interacting with Hormones 1.1.2.2. ␣7 Neuronal Nicotinic Acetyl-
7. Drugs interacting with Ion Channels choline Receptor Agonists
(=
/ Receptors) 1.2. Adenosine Receptors
8. Drugs interacting with Nerve Growth Factors 1.3. Adrenergic Receptors
9. Drugs interacting with Re-uptake Transporters 1.4. Angiotensin Receptors
(Psychostimulants) 1.5. Cannabinoid Receptors
10. Drugs interacting with Transcription Factors 1.6. Chemokine Receptors
11. Antioxidants 1.7. Dopamine Receptors
12. Metal Chelators 1.8. Endothelin Receptors
13. Natural Products 1.9. Estrogen Receptors
14. Nootropics (“Drugs without mechanism”) 1.10. GABA Receptors
15. Peptides 1.10.1. GABAA Receptors
16. Drugs preventing amyloid-␤ aggregation 1.10.2. GABAB Receptors
16.1. Ligands interacting with amyloid-␤ 1.10.3. GABAC Receptors
16.2. Inhibitors of serum amyloid P component 1.11. Galanin Receptors
binding 1.12. Glutamate Receptors
16.3. Vaccines against amyloid-␤ 1.12.1. AMPA Receptors
16.4. Antibodies against amyloid-␤ 1.12.1.1. Piracetam-type compounds
17. Drugs interacting with tau 1.12.1.2. AMPAkines
17.1. Small molecules preventing tau 1.12.1.3. Biarylpropylsulfonamides
aggregation 1.12.1.4. Benzothiadiazides
17.2. Ligands interacting with tau 1.12.1.5. 1-Hydroxyazoles
17.3. Vaccines against tau 1.12.2. NMDA Receptors
17.4. Antibodies against tau 1.12.3. Metabotropic Glutamate Receptors
18. Stem Cells 1.13. G-protein coupled Orphan Receptors
19. Miscellaneous 1.14. Histamine Receptors
In Part 1, drugs interacting with receptors are 1.15. Insulin Receptors
described, in Part 2 drugs interacting with enzymes, 1.16. Liver X Receptors
and in Part 3 drugs interacting with targets 3 to 10 and 1.17. Neurotensin Receptors
compounds and preparations of categories 11 to 19. 1.18. Nociceptin (ORL1) Receptors
1.19. Opioid Receptors
1. DRUGS INTERACTING WITH 1.20. Peripheral Benzodiazepine Receptors (PBRs)
RECEPTORS 1.21. Peroxisome Proliferator-activated Receptors
(PPARs)
Researchers have been investigating drugs interact- 1.22. Prostaglandin Receptors
ing with a wide variety of receptors in order to identify 1.23. Purinergic Receptors
valuable cognitive enhancers. These receptors (and 1.24. Receptor for Advanced Glycation End products
drugs) are: (RAGE)
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
1.25. Retinoid X Receptors
1.26. Ryanodine Receptors
1.27. Serotonin Receptors
1.27.1. 5-HT1A Receptor Agonists and Antag-
onists
1.27.2. 5-HT2 Receptor Antagonists
1.27.3. 5-HT3 Receptor Antagonists
1.27.4. 5-HT4 Receptor (partial) Agonists
1.27.5. 5-HT6 Receptor Antagonists
1.28. Sigma Receptors
1.29. Somatostatin Receptor Agonists
1.30. Sphingosine-1-phosphate Receptor Modula-
tors
1.31. Tachykinin Receptor
1.32. Tumor Necrosis Factor Receptor 1 Negative
Allosteric Modulators
1.1. Acetylcholine receptors
Acetylcholine is important for memory processes
([6–14]). The roles of cholinergic receptor subtypes
in cognition, emotion, and vigilance control were dis-
cussed recently [15]. After the publication of the
cholinergic hypothesis of AD by Bartus et al. in
1982 [16] showing by biochemical, electrophysiolog-
ical, and pharmacological evidence that cholinergic
dysfunction is responsible for age-related memory dis-
turbances, tremendous efforts have been undertaken by
academics and by researchers from the pharmaceutical
industry to find selective acetylcholine receptor ago-
nists (and acetylcholinesterase inhibitors) to counteract
cholinergic dysfunction. The search started with M1
selective orthosteric muscarinic acetylcholine receptor
(mAChR) agonists, was continued with efforts to find
selective presynaptic M2 receptor antagonists, shifted
later to nicotinic acetylcholine (partial) agonists and
since 2002 came back to allosteric M1 mAChR ago-
nists. Excellent reviews on the cholinergic system in
aging and neuronal degeneration have been published
[17–26]. The history of the cholinergic hypothesis was
also described [27].
1.1.1. Muscarinic acetylcholine receptors
(mAChRs)
mAChRs are widely expressed throughout the cen-
tral nervous system (CNS). Five mAChRs have been
cloned, of which M1 , M3 , and M5 mAChRs couple
via Gq/11 proteins to activated phospholipase-C and
mobilize intracellular calcium. M2 and M4 mAChRs
signal through Gi/o proteins to inhibit adenylate
cyclase and reduce intracellular concentrations of
cAMP [28]. Activation of mAChRs M1 and M3 stably
795
transfected into HEK cells leads to an increase of sol-
uble amyloid-␤ protein precursors A␤PP␣ and a con-
comitant reduction of amyloid-␤ (A␤) by activating
the ␣-secretase pathway [29, 30]. Muscarinic recep-
tor pharmacology and circuitry for the modulation of
cognition was described recently [31]. Muscarinic ago-
nists for the treatment of cognition in schizophrenia
was reviewed [32]. Loss of M1 mACh receptors exac-
erbated AD pathology and cognitive decline [33].
1.1.1.1. Orthosteric muscarinic acetylcholine M1
receptor agonists. All “first generation” muscarinic
cholinergic agonists interacted with the orthosteric
acetylcholine binding site. The orthosteric binding
pocket is a hydrophobic network of aromatic residues
contributed by the exofacial domains of transmem-
brane domains TM3, TM4, TM6, and TM7. Site
directed mutagenesis experiments have shown that the
binding of classic agonists such as carbachol is medi-
ated by two highly conserved residues tyrosine-381
and asparagine-382 in TM6 [34]. Additional studies
revealed that also Trp-101 (3.28), Tyr-404 (7.39), and
Tyr-408 (7.43) contribute to orthosteric agonist binding
[35].
Hundreds of (wo)man years went into syntheses and
characterization of M1 selective muscarinic cholin-
ergic agonists, five of which were followed up into
extended Phase III clinical trials before their develop-
ment was terminated due to unacceptable side effects
[28, 36]. The best known compounds are shown in
Fig. 1.
Cevimeline (AF-102B, SNK-508, Exovac,
hydrochloride hemihydrate, Israel Institute for
Biological Research; Fig. 1), a spiro-quinuclidine
derivative, is probably the best investigated selective
M1 mAChR agonist. It was in Phase III clinical trials
for the treatment of AD patients in the US, Japan,
and Israel. It is the only orthosteric acetylcholine
receptor agonist, which made it to the US and Japanese
markets in 2001 for the treatment of dry mouth of
patients suffering from Sjögren’s disease (xerostomia;
marketed by Snow Brand Milk Products and Daiichi
Pharmaceuticals [37–39]). The receptor profile of
cevimeline according to [40] is: M1 : EC50 = 23 nM,
Emax = 82%; M2 : EC50 = 1.04 ␮M, Emax = 98%; M1
selectivity over M2 : 78 fold; M3 : EC50 = 48 nM,
Emax = 75%; M1 selectivity over M3 : 2 fold; M4 :
EC50 = 1.31 ␮M, Emax = 50%; M1 selectivity over
M4 : 58 fold; M5 : EC50 = 63 nM, Emax = 43%; M1
selectivity over M5 : 3 fold. Cevimeline decreased
the levels of total A␤ in cerebrospinal fluid (CSF) of
patients with AD [41].
796 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 1. Structures of orthosteric muscarinic acetylcholine receptor ligands.
Xanomeline (LY-246708, monotartrate salt, Lilly
and Novo Nordisk; Fig. 1) was in Phase III clinical
trials for the treatment of AD patients in Denmark and
in Phase II in the US [42–44]. More recently, xanome-
line has also been tested as a novel treatment approach
of cognition deficits in schizophrenic patients [32,
45–51]. The receptor profile of xanomeline accord-
ing to [40] is: M1 : EC50 = 0.3 nM, Emax = 87%; M2 :
EC50 = 92.5 nM, Emax = 98%; M1 selectivity over M2 :
275 fold; M3 : EC50 = 5 nM, Emax = 111%; M1 selectiv-
ity over M3 : 15 fold; M4 : EC50 = 52 nM, Emax = 80%;
M1 selectivity over M4 : 154 fold; M5 : EC50 = 42 nM,
Emax = 68%; M1 selectivity over M5 : 126 fold. In ani-
mal experiments, xanomeline was also effective for the
treatment of neuropathic pain [52].
Milameline (CI-979, RU-35926, PD-129409,
hydrochloric acid salt; Parke-Davis, now Pfizer and
Roussel-Uclaf, now sanofi; Fig. 1) was in Phase III
clinical trials for the treatment of AD patients in the
US and Canada [53–57]. The receptor profile was not
published.
Alvameline (LU-25-109, L-(+)-tartrate salt; Lund-
beck; Forest; Fig. 1) was in Phase III clinical trial for
the treatment of patients with AD in Denmark and the
US [58, 59]. The receptor profile was not published.
Talsaclidine (WAL 2014 FU, fumarate salt,
Boehringer-Ingelheim; Fig. 1) was in Phase II clin-
ical trials for the treatment of patients with AD in
Germany and the US [60–62]. The receptor profile of
talsaclidine according to [40] is: M1 : EC50 = 18 nM,
Emax = 73%; M2 : EC50 = 1.535 ␮M, Emax = 86%; M1
selectivity over M2 : 87 fold; M3 : EC50 = 143 nM,
Emax = 76%; M1 selectivity over M3 : 8 fold; M4 :
EC50 = 1.02 ␮M, Emax = 64%; M1 selectivity over M4 :
57 fold; M5 : EC50 = 700 nM, Emax = 33%; M1 selec-
tivity over M5 : 40 fold. Talsaclidine stimulated the
non-amyloidogenic ␣-secretase processing of A␤PP
in vitro and in vivo [63, 64].
AF267B (NGX-267; TorreyPines Therapeutics
under license from Life Science Research Israel; Fig. 1)
was in Phase I clinical trials in the US for the treat-
ment of patients with AD. It is a spiro-piperidine
derivative from the laboratories of Abraham Fisher and
colleagues (Israel Institute for Biological Research,
Ness-Ziona [65–67]). The receptor profile of NGX-267
according to [40] is: M1 : EC50 = 30 nM, Emax = 82%;
M2 : EC50 = 1.57 ␮M, Emax = 85%; M1 selectivity over
M2 : 52 fold; M3 : EC50 = 44 nM, Emax = 109%; M1
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
selectivity over M3 : 1.5 fold; M4 : EC50 = 1.56 ␮M,
Emax = 55%; M1 selectivity over M4 : 52 fold; M5 :
EC50 = 850 nM, Emax = 34%; M1 selectivity over M5 :
28 fold. In an in depth study in triple transgenic mice
(A␤PPSWE , tauP301 L , and PS1M146 V knock-in), it was
shown that AF267B caused a selective activation of
ADAM17 (␣-secretase) thereby shifting A␤PP pro-
cessing towards the non-amyloidogenic pathway [68].
This shift is mediated by PKC and ERK 1/2 activation
[69]. In addition a decrease of GSK-3␤ activity led to
a reduction of tau pathology [68].
WAY-132983 (Wyeth, now Pfizer; Fig. 1), a highly
potent M1 mAChR agonist, reduced cognitive impair-
ment in rats at doses of 0.03 mg/kg/day [70, 71]. The
receptor profile of WAY-132983 according to [40] is:
M1 : EC50 = 0.3 nM, Emax = 96%; M2 : EC50 = 22 nM,
Emax = 97%; M1 selectivity over M2 : 78 fold; M3 :
EC50 = 2 nM, Emax = 114%; M1 selectivity over M3 :
5 fold; M4 : EC50 = 33 nM, Emax = 92%; M1 selectivity
over M4 : 116 fold; M5 : EC50 = 16 nM, Emax = 61%; M1
selectivity over M5 : 56 fold. The compound was also
evaluated in animal models of chronic pain [72].
Sabcomeline (SB-2022026, BCI-224; CEB-242,
Memric, hydrochloride salt; SK&B, now GSK; Fig. 1)
was in Phase III clinical trials for the treatment of
patients with AD in the UK. BrainCells (under license
from Proximagen and GSK) is developing sabcomeline
for the potential treatment of schizophrenia in Phase II
clinical trials since November 2011 [73, 74] (Thom-
son Reuters Pharma, update of March 29, 2012). The
receptor profile of sabcomeline according to [40] is:
M1 : EC50 = 0.2 nM, Emax = 83%; M2 : EC50 = 10 nM,
Emax = 95%; M1 selectivity over M2 : 48 fold; M3 :
EC50 = 0.1 nM, Emax = 95%; M1 selectivity over M3 :
0.6 fold; M4 : EC50 = 5.5 nM, Emax = 71%; M1 selec-
tivity over M4 : 26 fold; M5 : EC50 = 1 nM, Emax = 45%;
M1 selectivity over M5 : 5 fold. Sabcomeline produced
a greater response than xanomeline in releasing acetyl-
choline and dopamine in the medial prefrontal cortex
of rats at a dose of 1 mg/kg s.c. [46].
William S. Messer and coworkers at the Univer-
sity of Toledo have prepared the tetrahydropyrimidine
derivative MCD-386 (CDD-0102A; Fig. 1). The com-
pound was formulated as a controlled release tablet and
is evaluated in Phase I clinical trials by Mithridion.
FDA recently granted it an orphan drug designa-
tion to treat progressive supranuclear palsy [75–78].
A transdermal formulation of MCD-386 is also cur-
rently evaluated (Thomson Reuters Pharma, update of
May 31, 2012).
Potential back-up compounds are MI-09018, MI-
08-016/35, and MI-10-022 (Thomson Reuters Pharma,
797
updates of October 28, October 25, and Decem-
ber 6, 2011, respectively). The structures were not
communicated.
AZPET (FluoroPharma in collaboration with the
Massachusetts General Hospital, 18 F-RS-86, ex-
Sandoz, Fig. 1) is evaluated for the potential diagnosis
of AD (Thomson Reuters Pharma, update of June 19,
2012).
The development of many other orthosteric M1
selective mAChR agonists was also terminated in
earlier phases of clinical development (in alphabeti-
cal order): of A-72055 (Abbott Laboratories); AF-30
(Israel Institute for Biological Research [79–82]);
AF-150 and AF-151 (Israel Institute for Biolog-
ical Research and Snow Brand Milk Products
[66, 83–85]); arecoline transdermal patch (Cogent
Pharmaceuticals); CDD-34, CDD-0038, CDD-0097,
CDD-0098, CDD-190, CDD-0199-J, CDD-0235-J,
CDD-0304, CDD-0313, CDD-0316, CDD-0317, and
CDD-0322 (Mithridion under license from the Univer-
sity of Toledo); CI-1017 (Warner-Lambert, now Pfizer
[86–88]); CP-172607 (Pfizer); ET-126 (University of
Florence, a muscarinic M1 receptor antagonist [89]);
FP-7832 (Faust Pharmaceuticals, now Domain Ther-
apeutics); FPL-14995 and FPL-15467 (Fisons, now
sanofi; a M1 & M2 agonist and M3 antagonist); ita-
meline (RU-47213; Roussel-Uclaf, now sanofi [90]);
KAD-193 R (Kyorin Pharmaceuticals Co.); KW-6055
(Kyowa Hakko Kogyo Co. [91]); L-658903 (Merck
[92]); L-680648 (Merck [93]); L-687306 (Merck [94,
95]); L-689,660 (Merck [96]); L-705106 (Merck); LY-
354006 and LY-593093 (Lilly); McNa-343 (McNeill
Pharmaceuticals, now Johnson & Johnson); NC-11-
314, NC-11-1585, and NC-11-1607 (Novo Nordisk);
NGX-292 (TorreyPines Therapeutics); PD-151832
(CI-1017; Parke-Davis, now Pfizer); RS-86 (Sandoz,
now Novartis [97, 98]); SDZ-210-086 (Sandoz, now
Novartis [99]); SK-946 (Sanwa Kagaku Kenkyusho
[100–106]); SR-46559A (sanofi [107, 108]); T-588
(Toyama [109–117]); tazomeline (Lilly); thiopilo-
carpine (SDZ-ENS-163; Sandoz, now Novartis [44,
118–123]); U-80816 (Pharmacia & Upjohn, now
Pfizer); VRTX-3 (Vertex); and of YM-796 and YM-
954 (Yamanouchi, now Astellas [124–126]).
The main problem of all these compounds was
their limited selectivity for M1 mACh receptors.
Their interactions with M3 mAChRs caused unac-
ceptable side effects, such as severe gastrointestinal
distress, bradycardia, salivation, and sweating (sab-
comeline: M3 /M1 selectivity = 0.6; NGX-267: M3 /M1
selectivity = 1.5; cevimeline: M3 /M1 selectivity = 2;
WAY-132983, M3 /M1 selectivity = 5; talsaclidine:
798 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
M1, M3, M5
ACH (orthosteric)
binding site NH2
PLC
Gq
IP3
Ca2+
Fig. 2. Orthosteric and allosteric binding sites on the acetylcholine receptor [1302]. With permission from Elsevier.
M3 /M1 selectivity = 8; xanomeline, M3 /M1 selectiv-
ity = 15 [40]). The current opinion is that the orthosteric
binding site is highly conserved among mAChRs,
which makes the design of subtype selective com-
pounds extremely difficult [28, 35].
The development of the selective muscarinic M1
receptor antagonist LK-12 (All Russian Research
Institute of Pharmaceutical Chemistry) was also ter-
minated as was the development of the selective M4
receptor antagonist tropicamide (Harvard Medical
School [127]).
1.1.1.2. Allosteric muscarinic acetylcholine M1
receptor agonists. An important breakthrough was
achieved in 2002 at ACADIA Pharmaceuticals in
San Diego, where scientists screened a library of
145,000 structurally diverse small organic molecules
for agonist activity on M1 , M3 , and M5 muscarinic
receptors using a cell-based functional assay. They
identified allosteric agonists acting at a site removed
from the orthosteric site to directly activate the recep-
tor in the absence of acetylcholine, such as AC-42
(Fig. 3 [34, 128–130]), which was later optimized to
AC-260,584 (Fig. 3 [131]). The receptor profile of
AC-260,584 according to [40] is: M1 : EC50 = 2 nM,
Emax = 81%; M2 : EC50 = 470 nM, Emax = 68%; M1
selectivity over M2 : 220 fold; M3 : EC50 = 415 nM,
Emax = 41%; M1 selectivity over M3 : 195 fold (!!);
M4 : EC50 = >10 ␮M, Emax = 0%; M1 selectivity over
M4 : >5,000 fold; M5 : EC50 = 189 nM, Emax = 32%;
M1 selectivity over M5 : 89 fold.
Studies on M1 receptors with point mutations estab-
lished that the allosteric binding site is located adjacent
to the orthosteric site on the opposite face of residue
Trp-101 (3.28) [35, 128], see Fig. 2 [132, 133].
AC-262271 (Allergan under license from ACADIA
Pharmaceuticals) is being developed for the treatment
M2, M4
ACH (orthosteric)
Putative allosteric binding site
binding site(s)? NH2
AC
Gi
COOH ATP cAMP
COOH
of glaucoma in Phase I clinical trials since August 2007
(Thomson Reuters Pharma, update of March 28, 2012).
Its structure was not communicated.
AM-831 (ACADIA Pharmaceuticals in collabora-
tion with Meiji Seika, Tokyo) is a muscarinic M1
partial agonist with dopamine D2 and 5-HT2A antag-
onistic properties for the potential oral treatment of
schizophrenia and AD in Phase I trials in healthy vol-
unteers (Thomson Reuters Pharma, update of May 16,
2012). The structure was not communicated.
Glaxo SmithKline scientists found a highly selective
and systemically active M1 positive allosteric mod-
ulator (PAM), which did not activate the receptor
directly, but potentiated the activation of the receptor
by endogenous acetylcholine, i.e., 77-LH-28-1 [40]
does not cause down-regulation of M1 mACh recep-
tors [134, 135]. Further optimization led to the Phase
I compound GSK-1034702 (Fig. 3), which was well
tolerated [136, 137] (Thomson Reuters Pharma, update
of August 4, 2011).
There are currently several allosteric M1 mAChR
agonists in preclinical development (in alphabetical
order):
AstraZeneca (Fig. 3) presented gem-difluoro
bicyclics as novel M1 muscarinic receptor agonists,
which showed enhanced metabolic stability in com-
parison to the non-fluorinated analogues (Thomson
Reuters Pharma, update of April 18, 2012).
N-Desmethylclozapine (ACP-104; Fig. 3) was
identified as an allosteric modulator of mAChRs
[138, 139]. There is evidence that its cognition
enhancing effects derive from the muscarinic M1
receptor agonist interaction [46]. The receptor profile
according to [40] is: M1 : EC50 = 3 nM, Emax = 85%;
M2 : EC50 = 295 nM, Emax = 89%; M1 selectivity over
M2 : 107 fold; M3 : EC50 = 31 nM, Emax = 102%; M1
selectivity over M3 : 11 fold; M4 : EC50 = 1.23 ␮M,
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors 799

Fig. 3. Structures of allosteric muscarinic acetylcholine ligands.

Emax = 68%; M1 selectivity over M4 : 443 fold; M5 :
EC50 = 50 nM, Emax = 53%; M1 selectivity over M5 :
18 fold. Note that N-desmethylclozapine interacts with
the M1 mAChR at a third site positioned above the
orthosteric binding site [35, 128].
Heptares Therapeutics is investigating allosteric M1
subtype selective muscarinic acetylcholine agonists
for the potential treatment of schizophrenia and AD
(Thomson Reuters Pharma, update of April 26, 2012).
The structures were not communicated.
800 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 4. Structures of vincamine derivatives.
Lu AE51090 (Lundbeck, Fig. 3) is a compound with
“unprecedented selectivity” (EC50 at M1 : 61 nM and
Emax = 83%; Emax = 0%, 1%, 6%, and 1% at 10 ␮M
for M2 , M3 , M4 , M5 receptors, respectively). In a
delayed alternation Y-maze, the drug produced a sig-
nificant increase in correct alternation at doses of 10
and 20 mg/kg s.c. in mice [140].
Merck & Co conducted a screen on >1,000,000 com-
pounds to identify a PAM at M1 mAChRs, i.e., BQCA
(benzyl quinolone carboxylic acid, Fig. 3) [141].
BQCA reduced the concentration of acetylcholine
required to activate M1 receptors up to 129 fold. No
potentiation, agonism, or antagonism on the other sub-
types of mAChRs were observed up to 100 ␮M. BQCA
had no activity in >300 radioligand binding assays at
10 ␮M and did not significantly potentiate eight other
class A G protein coupled receptors at 37.5 ␮M. Stud-
ies in M1 (–/–) mice demonstrated that BQCA required
M1 to promote inositol phosphate turnover in primary
neurons and to increase c-fos and arc RNA expres-
sion and extracellular signal-regulated kinase (ERK)
phosphorylation in the brain. BQCA binds to Y179 in
the loop between transmembrane domains 4 and 5 and
to W400, which precedes transmembrane domain 7.
BQCA reversed scopolamine induced memory deficits
in contextual fear conditioning with doses of 10 and
30 mg/kg i.p., which neither TBPB (vide infra) nor AC-
42 (vide supra) did. BQCA increased blood flow to the
cerebral cortex and increased wakefulness while reduc-
ing delta sleep. BQCA induced ␤-arrestin recruitment
to M1 suggesting a role for this signal transduction
mechanism.
Scientists at Vanderbilt University also investi-
gated BQCA and found that it restored discrimination
reversal learning in a transgenic AD mouse model.
BQCA regulated non-amyloidogenic A␤PP process-
ing in vitro suggesting that M1 PAMs have the potential
to provide both symptomatic and disease modifying
effects in AD patients [142].
Merck scientists presented a more advanced com-
pound (Fig. 3) with good bioavailabilities in rats and
dogs of 68 and 62%, respectively (Thomson Reuters
Pharma, update of May 31, 2012). For excellent medic-
inal chemistry, see [143–150].
TBPB (Vanderbilt University, Fig. 3) is a PAM at
muscarinic M1 receptors, which had effects on the
processing of A␤PP toward the non-amyloidogenic
pathway [151–153]. Further optimization efforts led
to VU-0357017 (ML-071) and VU034572 (Fig. 3)
[154–158].
ML169 (VU-0405652; Vanderbilt University;
Fig. 3) is an optimized, brain penetrant M1 PAM
based on VU0366369 (ML137) [159, 160].
Vanderbilt University and Seaside Therapeutics are
also investigating allosteric M1 mAChR antagonists
for the potential treatment of fragile X syndrome
and autism. VU0415248 (Fig. 3) is the most recent
optimized compound based on VU0255035 (ML012;
Fig. 3) [161, 162].
The development of ACP-104 (N-
desmethylclozapine) and PCAP-1 and PCAP-2
(all ACADIA Pharmaceuticals) were terminated.
1.1.1.3. Vincamine-type compounds. In an early
review [5], vincamine-type compounds were described
as a chemical class, because the mechanism of
their cognition enhancing effects was unknown.
Surprisingly, it turned out that (–)-eburnamonine
(Vinburnine; Fig. 4) and vincamine (Fig. 4) acted as
allosteric M1 to M4 muscarinic ligands [163–166].
The affinities to the subtypes of mAChRs are modest
(measurements of binding of [3 H]NMS in the presence
of increasing concentrations of the allosteric ligands,
for vincamine: M1 : KA = 17.3 ␮M, M2 : 8.12 ␮M,
M3 : 1.85 ␮M, M4 : 58.9 ␮M; for (–)-eburnamonine:
M1 : KA = 7.54 ␮M, M2 : 68.9 ␮M, M3 : 6.67 ␮M, M4 :
23.7 ␮M [164].
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 5. Structures of muscarinic acetylcholine M2 receptor antagonists.
Medicinal chemists of Gedeon Richter explored
trans-vincamine derivatives and identified RGH-
10885 (Fig. 4) as a novel cognition enhancer active
at an oral dose of 5 mg/kg in rats, which also inhibited
lipid peroxidation [167]. Its development was termi-
nated as was the development of Vintoperol (RT-3003;
Gedeon Richter [168, 169]), Vinconate (OM-853;
Omnium [170–180]), and Apovincamine, the 2-
nitroxyethyl ester of (+)-eburnamenine-14-carboxylic
acid (VA-045; Taisho [181–188]), which protected
mice against traumatic brain injury-induced retrograde
and anterograde amnesia [189, 190].
1.1.1.4. Muscarinic acetylcholine M2 receptor
antagonists. An alternative approach to achieve
improved cholinergic transmission is to antagonize
central presynaptic muscarinic M2 receptors leading
to an increased release of acetylcholine. This approach
was mainly followed up by scientists at Schering-
Plough, Boehringer-Ingelheim, GSK, and Roche and
was described in an excellent review [36]. For earlier
work, see [191]. Best known compounds are BIBN-99
(Boehringer-Ingelheim; Fig. 5; M2 : Ki = 9 nM, ratio
M1 /M2 = 26) and SCH-217443 (Schering-Plough;
Fig. 5; M2 : Ki = 0.4 nM, ratio M1 /M2 = 623, ratio
M3 /M2 = 250, ratio M4 /M2 = 35, ratio M5 /M2 = 58).
SCH-217443 showed excellent oral bioavailability
and cognition enhancing effects in rats at low oral
doses of 0.001, 0.01, and 0.1 mg/kg. As M2 receptors
are also present in cardiac tissue, an increased heart
rate in rats was observed at doses of 3 mg/kg p.o.
[192].
801
It appears that safety concerns about potential
cardiac side effects [28] led to the termination of
the development of BIBN-140, SCH-57790, SCH-
72788, and SCH-226206. Also himbacine analogues
were actively pursued by scientists from Kyorin
and Schering-Plough. Their development was also
abandoned.
1.1.2. Nicotinic acetylcholine receptors
Nicotinic acetylcholine receptors (nAChRs) are
ion channel receptors belonging to the same class
as 5-HT3 , GABAA , and strychnine-sensitive glycine
receptors [193]. Each subunit has a large N-terminal
extracellular domain, a transmembrane domain com-
prising four segments (TM1-TM4) and a small
C-terminal. They form pentamers with the M2 domain
at the inside of the channel, which is permeable to Na+
and K+ ions. The nAChRs are encoded by 17 genes. Of
these nine ␣ subunits (␣2–␣10) and three ␤ subunits
(␤2–␤4) are expressed in the brain [194–196]. >90%
of the nAChR in the CNS contain ␣4 and ␤2 subunits
forming ␣-bungarotoxin insensitive receptors. Another
subtype consists of a homopentamer of ␣7 subunits,
␣-bungarotoxin sensitive receptors [197]. The acetyl-
choline binding site lies at the interface between an
␣-type subunit (the principal component) and a non-
␣-type subunit (the complementary component). In the
␣4␤2 receptor (consisting of 2 ␣4 and 3 ␤2 subunits)
there are two, and in the ␣7 homopentamer there are
five ACh binding sites. The localization of nAChRs
in the hippocampus was elucidated [198]. Functional
brain imaging of nicotinic effects on higher cognitive
802 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

Fig. 6. ␣4␤2 and ␣3␤4 nicotinic acetylcholine receptor agonists.

processes have been reported [199]. The topic nico-
tinic receptors, A␤, and synaptic failure was discussed
[200]. Excellent reviews on selective nAChR agonists
as potential therapies to treat cognitive impairment
associated with schizophrenia and AD were published
recently [201, 202].
1.1.2.1. α4β2 and α3β4 nicotinic acetylcholine
receptor agonists. ␣4␤2 nAChRs have a role in
cognitive function [203, 204]. Medicinal chemists
and pharmacologists succeeded to identify agonists
with improved safety and therapeutic profiles in
comparison to nicotine [205]. Treating cognitive
deficits of schizophrenic patients with ␣4␤2 neuronal
nicotinic receptor agonists was discussed [206]. ␣6␤2
and ␣4␤2 nAChRs as drug targets for Parkinson’s
disease were reviewed [207]. Peroxisome proliferator-
activated receptor (PPAR)␣ ligands are important
negative modulators of ␣4␤2 nAChRs on dopamin-
ergic neurons [208].
Varenicline (Chantix, Champix; CP-526555;
Pfizer; Fig. 6) is a partial agonist for ␣4␤2 nAChRs
and a full agonist at ␣7 neuronal nicotinic receptors
[209]. The drug was launched in 2006 as an aid to
smoking cessation treatment [210–227]. Sales in 2011
were USD 720 million. Partial agonists at the ␣4␤2
subtype in the mesolimbic system stimulate dopamine
release to reduce craving when quitting, whereas the
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
antagonistic properties inhibit nicotine reinforcement
when smoking [228]. A Phase II clinical trial in
subjects with mild to moderate AD has started in early
2010. However, by February 2011 the development
of varenicline tartrate had been discontinued for
the treatment of cognition deficits in AD patients
(Thomson Reuters Pharma, update of June 25, 2012).
Pozanicline (ABT-089; Abbott; Fig. 6) was already
characterized preclinically in 1997 [229, 230]. The
drug was tested in AD, ADHD, schizophrenia, and
smoking cessation. The indication schizophrenia was
abandoned. Two Phase II trials in children afflicted by
ADHD gave negative results. Efficacy and safety of
ABT-089 in adults with ADHD was reported [231]
(Thomson Reuters Pharma, update of February 8,
2012).
Ispronicline (TC-1734; AZD-3480; Targacept and
AstraZeneca; Fig. 6) is developed for potential oral
treatment of AD and ADHD [232–239]. Results of a
Phase IIb AD trial were reported [240]. The drug was
also under development for schizophrenia-associated
cognitive deficits, but failed to meet the primary end-
points [241] (Thomson Reuters Pharma, update of May
17, 2012).
AZD-1446 (TC-6683; AstraZeneca in collaboration
with Targacept) is tested in clinical Phase II trials both
in patients suffering from AD and from ADHD. In
January 2012 AstraZeneca decided to advance the drug
in AD. It appears that a Phase II trial with AZD-1446
as an adjunct treatment to donepezil will be initiated in
patients with mild to moderate AD (Thomson Reuters
Pharma, update of June 6, 2012). The structure was not
disclosed.
Lobeline (derived from lobelia inflata; Ceptaris
Therapeutics, formerly Yaupon Therapeutics, Fig. 6) is
being developed for the potential treatment of metham-
phetamine addiction and ADHD in Phase II trials since
July 2008. By January 2010, the trials in both indica-
tions were completed [242, 243] (Thomson Reuters
Pharma, update of January 6, 2012).
Sofinicline (ABT-894; Abbott under license from
NeuroSearch; Fig. 6) was in a Phase II trial in adults
with ADHD since January 2007. In June 2008 it was
reported that the drug was safe and generally well tol-
erated. A formulation of sofinicline for potential use in
a Phase II dose-finding study in children with ADHD
was optimized. Previously the drug was evaluated as
an analgesic [244] (Thomson Reuters Pharma, update
of April 18, 2012).
ABT-560 (Abbott under license from NeuroSearch)
is an ␣4␤2 subtype selective nAChR agonist in Phase I
clinical trials since July 2007 (Thomson Reuters
803
Pharma, update of January 2, 2012). The structure of
ABT-560 was not communicated.
There are several ␣4␤2 subtype selective nAChR
agonist in preclinical evaluation (in alphabetical
order):
NS-9283 (A-969933; NeuroSearch in collabora-
tion with Abbott Laboratories; Fig. 6) is a selective
␣4␤2 nACh receptor PAM for the potential treatment
of neurological disorders including pain and cogni-
tive disorders [245, 246] (Thomson Reuters Pharma,
update of December 8, 2011).
S-35836-1 (Servier; Fig. 6) and S-38232 are a new
cyclopropanamine derivatives for the potential treat-
ment of age-related cognitive disorders [247, 248]
(Thomson Reuters Pharma, update of December 6,
2011).
SAZETIDINE-A (AMOP-H-OH; PsychoGenics
in collaboration with Prof. A. P. Kozikowski and
coworkers at the University of Illinois at Chicago,
Fig. 6) was identified as a potent agonist acting at
the high sensitivity ␣4␤2 nAChR isoform [249–251]
(Thomson Reuters Pharma, update of March 09,
2012).). Axeuron is evaluating the drug for smoking
cessation (Thomson Reuters Pharma, update of Febru-
ary 27, 2012).
Compound 64 (Prof. A. P. Kozikowski and cowork-
ers at the University of Illinois at Chicago, Fig. 6)
showed high radioligand binding affinity and selectiv-
ity for rat ␣4␤2 nAChR with a Ki value of 1.2 nM and
a 4,700-fold selectivity for ␣4␤2 over ␣3␤4 nAChRs.
Compound 64 exhibited antidepressant-like effects
in the mouse forced swim test [252]. For isoxazole
analogues of sazetidine, see [253, 254]; for chiral
cyclopropane derivatives [255].
SR-16584 (SRI International, Fig. 6) and SR-17080
are non-competitive ␣3␤4 nAChR antagonists. SR-
17080 has a Ki value of 2.6 nM at ␣3␤4 nAChRs
compared with 476 nM at ␣4␤2 receptors. The aim
is potential treatment of AD [256] (Thomson Reuters
Pharma, update of January 25, 2011).
SUVN-F91201 (Suven Life Sciences) is an ␣4␤2
nAChR agonist with a Ki of 24.7 nM and an oral
bioavailability in rats of 57% for the potential treatment
of AD (Thomson Reuters Pharma, update of February
8, 2012). The structure was not communicated.
SUVN-911 (Suven Life Sciences) is an oral ␣4␤2
nAChR antagonist, for the potential treatment of mood
disorders and major depressive disorders. Other ␣4␤2
nAChR antagonists are evaluated for the potential
treatment of schizophrenia, pain, and cognitive disor-
ders (Thomson Reuters Pharma, update of February 8,
2012). Structures were not communicated.
804 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Carbon-11 labeled pyridyl ethers for in vivo imaging
of ␣4␤2 nAChRs in brain were described [257].
The development of several well-known com-
pounds was terminated (in alphabetical order): of
A-82695 (Abbott Laboratories [258–260]), ABT-
418 (Abbott [261–268]), altinicline (SIB-1508Y;
Sibia, now Merck for the indication of Parkinson’s
disease [269–271]), ATG-001 (CoMentis), DBO-
83 (University of Florence [272, 273]), dianicline
(SSR-591813; sanofi for the indication of smoking
cessation [274–276]), of a nicotine patch (Japan
Tobacco), rivanicline (RJR-2403, TC-2403; Targa-
cept, previously RJ Reynolds Tobacco [277–281]),
RJR-1401 (RJ Reynolds Tobacco), of TC-1827,
TC-2429 (RJR-2429), TC-2559, and TC-4959 (AVE-
3183; Targacept in collaboration with Aventis, now
sanofi), of TC-5214 (S-(+)-mecamylamine; Targacept
and AstraZeneca; a selective ␣4␤2 nAChR antagonist
[282–284]), of tebanicline (ABT-594; Abbott [285]
and A-366833 [286]), both for the indication of pain
and neuropathy and of UB-165 (University of Bristol
[287–290]).
1.1.2.2. Alpha7 nicotinic acetylcholine receptor
agonists. ␣7 nAChRs are highly expressed in the
hippocampus. Gene knockout and antisense experi-
ments have shown a role for ␣7 nAChRs in learning
and memory ([291–293]. Deletion of the ␣7 nAChR
gene improves cognitive deficits in a mouse model of
AD [294]. For excellent reviews, see [295–307]. For
an in depth review on targeting ␣7 nAChRs for the
treatment of schizophrenia, see [308].
ABT-126 (Abbott Laboratories) is an ␣7 neuronal
nicotinic receptor modulator for the potential treat-
ment of AD and for cognitive deficits in schizophrenia
(CDS) in Phase II clinical trials. In October 2009 a
multicenter, randomized, double-blind, placebo- and
active-controlled Phase II was initiated in 274 mild
to moderate AD patients in the US, Bulgaria, the
Czech Republic, Slovakia, South Africa, and the
UK (NCT00948909). In March 2010 a randomized,
double-blind, placebo controlled Phase II study in
210 CDS patients began in the US (NCT01095562).
In March 2009 a randomized, double-blind Phase I
trial began to assess the safety, tolerability, and phar-
macokinetics of ABT-126 (20 mg four times a day
(qid) for 10 days and 35 mg qid for 21 days in 30
elderly subjects; NCT00867399). In February 2012
a randomized, double-blind, placebo and active con-
trolled Phase II study to evaluate the efficacy and
safety of ABT-126 in patients with mild to moder-
ate AD (n = 410; NCT01527916) was expected to start
(Thomson Reuters Pharma, update of March 13, 2012).
The structure of ABT-126 was not communicated.
EVP-6124 (MT-4666, EnVivo under license from
Bayer and Mitsubishi Tanabe Pharma; Fig. 7) is an ␣7
nAChR partial agonist in Phase IIb clinical trials for
the treatment of cognition deficits in patients with AD
since May 2010 and in schizophrenia patients since
January 2010; Thomson Reuters Pharma, update of
June 14, 2012). An improvement of working and recog-
nition memory in rodents at doses of 0.3 to 1 mg/kg p.o.
was recognized [309]. Additional in vitro and in vivo
characterization was disclosed recently [310].
A potential follow-up compound is EVP-4473
(Thomson Reuters Pharma, update of Dec. 23, 2011).
The structure of EVP-4473 was not communicated.
GTS-21 (DMXB; CoMentis licensed from the Uni-
versity of Florida; Fig. 7) is an ␣7 nAChR partial
agonist in Phase II clinical trials for the treatment of
AD, CDS, and ADHD [311–317] (Thomson Reuters
Pharma, update of March 14, 2012).
TC-5619 (Targacept, Fig. 7) is a full agonist at ␣7
nAChRs and is currently in Phase II clinical trials for
the treatment of schizophrenia in the US and Eastern
Europe (n = 450) since December 2011. Another Phase
II trial in 80 patients with inattentive-predominant
ADHD was initiated in the US in November 2011. For
efficacy in animal models, see [318] (Thomson Reuters
Pharma, update of June 6, 2012).
ABT-272 (Abbott Laboratories) is an ␣7 nAChR
modulator for the potential treatment of pain in Phase I
clinical trials (Thomson Reuters Pharma, update of
November 24, 2011). The structure of ABT-272 was
not communicated.
There are many selective ␣7 neuronal nicotinic
receptor (partial) agonists in preclinical evaluation (in
alphabetical order):
A-867744 (Abbott Laboratories; Fig. 7) and ABT-
779 are PAMs of the ␣7 nAChR [319, 320]; Thomson
Reuters Pharma, update of September 27, 2011).
Extensive preclinical characterization of A-582941
(Fig. 7) described the broad-spectrum cognition-
enhancing properties [321] (Thomson Reuters Pharma,
update of October 21, 2011).
␣7 nAChR agonists (Naprogenix in collaboration
with Ceptaris Therapeutics, formerly Yaupon Phar-
maceuticals) are plant extracts discovered by plant-
genomics technology (Thomson Reuters Pharma,
update of January 6, 2012). In a second program,
N-methyl-D-aspartic acid (NMDA) receptor and ␣7
nAChR inhibitors are evaluated.
APL-1 (Galantos Pharma) is a nAChR
allosteric potentiating ligand (nAChR APL), which
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors 805

Fig. 7. ␣7 nicotinic acetylcholine receptor agonists.

specifically targets nAChR ␣7 subtypes for the AZT-2 (Lundbeck) is an ␣7 nAChR PAM for
potential treatment of AD (Thomson Reuters Pharma, the potential treatment of cognitive dysfunctions
update of February 6, 2012). The structure was not (Thomson Reuters Pharma, update of December 6,
communicated. 2011). The structure was not communicated.
806 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Bio-Link is investigating positive allosteric ␣7
nAChR modulators for the potential treatment of
cognitive disorders (Thomson Reuters Pharma, update
of February 13, 2012). The structures were not
communicated.
BMS-902483 (Bristol-Myers Squibb, Fig. 7) is a
partial ␣7 nAChR agonist with an EC50 of 9.3 nM.
It demonstrated excellent brain penetration and ␣7
nAChR occupancy at low plasma concentrations in
rodents. The compound showed hepatotoxicity in dogs
(Thomson Reuters Pharma, update of April 3, 2012).
BNC-1881 (Bionomics) is a PAM of ␣7 nAChR
for the potential memory improvement treatment in
AD and schizophrenia (Thomson Reuters Pharma,
update of June 28, 2012). The structure was not
communicated.
Cholinergic therapeutics (Ophidion) are siRNA
mediated lynx-1 modulators, which regulate ␣7
nACh receptors [322–324] (Thomson Reuters Pharma,
update of June 15, 2012). Structures were not
communicated.
JNJ-1930942 (Johnson & Johnson; Fig. 7) is a
highly selective PAM of ␣7 nAChRs for the treatment
of CDS, Parkinson’s disease, AD, and ADHD. It does
not act on ␣4␤2, ␣3␤4 nAChRs, or on the related 5-
HT3 channel. It increased peak and net charge response
to choline and acetylcholine mainly by affecting recep-
tor desensitization characteristics [325] (Thomson
Reuters Pharma, update of February 15, 2011).
11 C-NS-12857 and 11 C-NS-14492 (NeuroSearch,
University of Copenhagen; Fig. 7) are positron emis-
sion tomography (PET) ligands for the assessment of
neurological disorders including AD and schizophre-
nia (Thomson Reuters Pharma, update of November
16, 2010).
PheTQS (Promaxigen under license from GSK;
Fig. 7) showed an EC50 value of 20 nM as PAM of ␣7
nAChRs in transfected GH41 C cells. One compound
of this series is in Phase I trials for cognitive disorders
since March 2012 (Thomson Reuters Pharma, update
of May 10, 2012).
S-24795 (Servier; Fig. 7) inhibited binding of A␤
to ␣7 nAChRs [326–332] (Thomson Reuters Pharma,
update of March 7, 2011).
SEN-34625/WYE-103914 (Siena Biotech and
Pfizer; Fig. 7) is an optimized agonist at ␣7 nAChRs
with an EC50 of 70 nM with excellent in vitro and in
vivo profiles [333, 334] (Thomson Reuters Pharma,
update of January 10, 2012).
SEN-15924/WAY-361789 (Siena Biotech and
Pfizer; Fig. 7) is a potent, selective, and orally active
full agonist at ␣7 nAChRs with excellent efficacy in
rodent behavioral cognition models, such as novel
object recognition and auditory sensory gating [335].
A previous compound SEN-12333/WAY-317538 was
abandoned [336].
SKL-A4R (SK Biopharmaceuticals, formerly SK
Life Science) is a novel ␣7 nAChR partial agonist
displaying pro-cognitive and neuroprotective effects
(Thomson Reuters Pharma, update of March 19, 2012).
The structure was not communicated.
UCI-40083 (University of California at Irvine;
Fig. 7) is an isoxazole-acetamide derived ␣7 nAChR
PAM for the potential treatment of CDS and ADHD
[337]. At the 243rd ACS Meeting in San Diego in
March 2012, a novel pyridine structure was disclosed
(Fig. 7; Thomson Reuters Pharma, update of June 8,
2012).
Dual ␣7 nicotinic acetylcholine receptor activa-
tors and BACE-1 inhibitors are investigated in a
program by the University of Maryland [338] (Thom-
son Reuters Pharma, update of February 24, 2012).
The development of several well-known compounds
was terminated, e.g., of ABT-107 (Abbott [339–341]),
AR-R-17779 (Astra Arcus, now AstraZeneca),
AZD-0328 (AstraZeneca [342–344]), AZD-6319
(AstraZeneca), CP-810123 (PNU-120596; Pfizer
[345–347]), facinicline (MEM-3454, R3487;
RO5313534; Memory Pharmaceuticals, now Roche
[348, 349]), JN403 (Novartis [350–352]) and JN711
(Novartis [353, 354]), MEM-63908 (RG-4996; Mem-
ory Pharmaceuticals, now Roche), NNC-90-0270
(Novo Nordisk), PHA-543613 and PHA-568487
(both Pfizer), SAR-130479 (sanofi), SIB-1553A,
SIB-1663, SIB-1765F, SIB-1926, and SIB-3182
(Sibia, now Merck [355–362]; for the treatment
of cognitive dysfunctions see [197]), SSR-180711
(sanofi [347, 363]), W-56203 (Mitsubishi Tanabe
Pharma), and of XY-4083 (Xytis).
1.2. Adenosine receptors
Adenosine receptors have been implicated in the
modulation of cognitive functions. The assessment of
adenosine receptor antagonists for the treatment of
cognitive dysfunction in animal studies was reviewed
[364]. In particular selective inactivation of A2A
adenosine receptors enhanced learning and memory
functions [365, 366]. Mice lacking A2A adeno-
sine receptors displayed improved spatial recognition
memory [367].
The best known A2A adenosine receptor antago-
nist is caffeine (25,381 entries in PubMed as of May
28, 2012). The KD values of caffeine at human A1
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
receptors are 12 ␮M, at A2A receptors 2.4 ␮M, at A2B
receptors 13 ␮M, and at A3 receptors 80 ␮M [368].
Experiments were carried out in wild-type and in
A1 and A2A knock-out mice at doses of 15, 10, and
5 mg/kg i.p., of caffeine. In wild-type mice the dose of
15 mg/kg significantly increased wakefulness by 1.5,
2.9, and 2.1 fold during the first, second, and third
hour after injection, respectively. In contrast, in A2A
knockout mice, the dose of 15 mg/kg did not show any
change in time spent in wakefulness, whereas A1 R
knockout mice showed the same increase in wake-
fulness as wild-type mice confirming that the arousal
effect of caffeine is due to A2A receptors [369–371].
The psychomotor stimulant effects of caffeine are gen-
erated by affecting a particular group of projection
neurons located in the striatum expressing high levels
or A2A adenosine receptors [372]. A1 –A2A recep-
tor heteromers were identified in the striatum [373].
Caffeine has the ability to release the pre- and postsy-
naptic brakes that adenosine imposed on dopaminergic
neurotransmission [374].
Astrid Nehlig [3] reviewed the topic: “Is caffeine a
cognitive enhancer?” Caffeine facilitated learning in
tasks in which information is presented passively. In
tasks in which material is learned intentionally, caf-
feine had no effect. Caffeine facilitated low-difficulty
performance in low-load memory tasks and impaired
it on high-load tasks, probably due to over-arousal.
In the longitudinal Three City Cohort Study including
4,197 healthy women and 2,820 healthy men over 65
years, women consuming over 3 cups of caffeine daily
for over 4 years showed less decline in verbal retrieval
and visuospatial memory than women consuming one
cup or less. The protective effect of caffeine increased
with age with a maximal effect in women over 80
years. No relation was found between caffeine intake
and cognitive decline in men [375]. Caffeine, but not
theophylline, exerted disease-modifying effects in AD
mice including a direct reduction of A␤ production
through suppression of both ␤-and ␥-secretase levels
[376–378]. This may be due to increased plasma levels
of granulocyte-colony stimulating factor [379]. High
blood caffeine levels in patients with mild cognitive
impairment (MCI) are linked to a lack of progression
to dementia [380].
Rabbits fed on a 2% cholesterol-enriched diet
showed enhanced levels of A␤ and tau phosphoryla-
tion and increased levels of reactive oxygen species
and isoprostanes. Caffeine at 0.5 and 30 mg/kg per
day in drinking water reduced the cholesterol-induced
increase in A␤, phosphorylated tau, and oxidative
stress levels suggesting that even very low doses
807
of caffeine might protect against sporadic AD-like
pathology [381]. Rifampicin and caffeine caused an
upregulation of the low-density lipoprotein recep-
tor related protein-1. The brain efflux index of A␤
in rifampicin and caffeine treated mice was sig-
nificantly higher (82% and 80%, respectively) than
the brain efflux index of control mice (62%). It
appears that a yet to be identified transporter/receptor
plays a significant role in A␤ clearance, which is
upregulated by rifampicin and caffeine [382]. Caf-
feine at 10 mg/kg improved memory recognition
on scopolamine-induced impairment of memory in
mice [383]. In the novel object recognition task,
pre-treatment with caffeine prevented disruption of
short- and long-term memory by scopolamine. In the
inhibitory avoidance task caffeine prevented short-
term, but not long-term, memory disruption by
pre-training with scopolamine. These results con-
firmed previous data in humans [384].
In a very large prospective study in 229,229 men and
173,141 women during 1995 and 2005, coffee con-
sumption was found to be inversely associated with
total and cause-specific mortality [385].
Some effects of caffeine are unrelated to interac-
tions with adenosine receptors. Caffeine also acts as a
competitive, non-selective phosphodiesterase inhibitor
[370, 386].
Tozadenant (SYN-115; Biotie Therapies Holding,
formerly Synosia Therapeutics under license from
Roche; Fig. 8) is a potent and selective A2A receptor
antagonist for the potential treatment of Parkinson’s
disease in Phase IIb clinical trials since April 2011
[387] (Thomson Reuters Pharma, update of May 29,
2012).
Shire (under license from Heptares Therapeutics)
is investigating a series of A2A receptor antagonists
for the potential treatment of Parkinson’s disease, cog-
nition deficits, and other CNS disorders (Thomson
Reuters Pharma, update of May 2, 2012).
The development of a potent adenosine A1 and A2A
receptor dual antagonist ASP-5854 (Astellas Pharma)
was terminated [388, 389].
1.3. Adrenergic receptors
The serotonergic and adrenergic mechanisms of
cognition have been reviewed [390]. Long-term ␣1A -
adrenergic receptor stimulation improved synaptic
plasticity, cognitive function, mood, and longevity
in transgenic mice [391]. The beneficial effects
of desipramine on cognitive function of chroni-
cally stressed rats are mediated by ␣1 -adrenergic
808 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

Fig. 8. An adenosine A2A receptor antagonist and memory enhancing angiotensin AT1 receptor antagonists.

receptors [392]. The ␣2 -adrenoceptor agonist guan-
facine improved performance in an attention test in
aged Rhesus monkeys [393]. The roles of ␤-adrenergic
receptors in AD were discussed [394].
Buflomedil (Loftyl, Laboratoire L. Lafon, later
Cephalon, now Teva) is an ␣1A /␣1B adrenocep-
tor antagonist (Ki = 4 ␮M and 6.84 ␮M, respectively
[395]) with partial calcium channel antagonist activity
launched for the treatment of peripheral vascular dis-
ease and cognitive disorders [396–401]. An interesting
case study was presented [402].
ORM-12741 (Orion Corporation) is an ␣2 C adreno-
ceptor antagonist for the potential treatment of
neurological diseases such as AD and Raynaud’s
disease. By April 2011, a randomized, double-blind,
placebo-controlled Phase II trial in AD patients
(n = 99) was started in Finland and is expected to termi-
nate in June 2012. A Phase II trial in Raynaud’s disease
was initiated in the UK (n = 18) in August 2011 (Thom-
son Reuters Pharma, update of February 21, 2012). The
structure was not communicated.
Carvedilol, an ␣1 , ␤1 and ␤2 adrenoceptor blocker,
re-established long term potentiation in mouse models
of AD [403–406].
The development of dabelotine (S-12024-2,
Servier), an adrenoceptor agonist and nootropic agent,
was discontinued [407–412], as was the develop-
ment of idazoxan (Pierre Fabre), an ␣2 adrenoceptor
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
antagonist [413], of 5-fluoro-methoxy-idazoxan F-
14413 (Pierre Fabre), of S-32212, S-34324 and
S-35966 (Servier, dual ␣2 adrenoceptor antagonists
and serotonin and noradrenaline re-uptake inhibitors)
and of SDZ-NVI-085 (a selective, centrally act-
ing ␣1 adrenoceptor agonist; Sandoz, now Novartis
[414–419].
1.4. Angiotensin receptors
1,818 papers have been published on the brain
renin-angiotensin system (PubMed citations as of
May 28, 2012).There are plausible explanations for
the cognitive facilitation noted in human clinical tri-
als conducted with AT1 antagonists [420, 421]. The
formation of angiotensin II interferes with memory
acquisition. Preventing the formation of angiotensin II
should facilitate cognitive processing. Preventing the
formation of angiotensin II also releases the inhibi-
tion of potassium-induced exocytosis of acetylcholine.
Preclinical findings of the brain renin-angiotensin sys-
tem in cognitive function and implications for the
prevention and treatment of dementia were commu-
nicated [422, 423]. An AT1 receptor blocker may have
greater cognition protective effects that angiotensin-
converting-enzyme (ACE) inhibitors [424]. The effects
of renin-angiotensin system blockade on cognitive
function in patients aged 55 years and older were inves-
tigated [425]. The effects of the ACE inhibitor ramipril,
the angiotensin-receptor blocker telmisartan, and a
combination of the drugs were evaluated in 25,620
patients. Meta-regression analysis did not show any
benefits of blood-pressure lowering on cognition over
several years of treatment. The current standing of the
angiotensin hypothesis in AD was published in 2012
[426].
Losartan (DUP-753; Merck, launched in 1994;
Fig. 8) is a brain penetrating selective AT1 recep-
tor antagonist. Losartan administered intranasally to
A␤PP/PS1 transgenic mice for two months decreased
A␤ plaques by 3.7 fold [427]. Losartan also showed
memory-enhancing properties in an active avoidance
task in mice [428, 429], which is due to involvement
of the cholinergic system [430]. Losartan signifi-
cantly increased the score of the word list memory
and the word list recall test in elderly hypertensive
patients [431]. Cognitive enhancement following acute
losartan in normotensive young adults was reported
[432].
Candesartan (Takeda, launched in 1998; Fig. 8)
improved memory decline in mice [433] and in older
patients with hypertension [434].
809
Telmisartan (Boehringer Ingelheim, launched in
1999; Fig. 8) prevented A␤ caused cognitive decline,
which may be partly due to an activation of PPAR-␥
[435–439]. It improved cognitive function in elderly
hypertensive patients [440].
Valsartan (Novartis, launched in 1996; Fig. 8) low-
ered brain A␤ protein levels [441].
Also Eprosartan (GSK, launched 1999; Fig. 8) pen-
etrated the blood-brain barrier [442]) as did Irbesartan
(sanofi, launched 1997; Fig. 8) [443, 444].
The development of RS-66252 (an angiotensin
1 receptor antagonist; Syntex, now Roche) and of
WSU-2088 (an angiotensin 4 receptor agonist of the
Washington State University) has been terminated.
1.5. Cannabinoid receptors
The endocannabinoids and the CB1 receptors have
been implicated in the control of cognition [445–447].
Cannabinoids and prefrontal cortical functions have
been studied [448]. Significantly lower levels of
the endocannabinoid anandamide and its precursor
1-stearoyl-2-docosahexaenoyl-sn-glycero-phospho-
ethanolamine-N-arachido-noyl (NArPE) were found
in postmortem brain samples from AD patients in
comparison to brains from control subjects [449].
Anandamide and NArPE levels in midfrontal cortex of
the study subjects inversely correlated with levels of
A␤42 while showing no association with A␤40 levels,
amyloid plaque load, or tau protein phosphorylation.
Dronabinol (ultrapure THC, Namisol; Echo Phar-
maceuticals), a natural product and cannabinoid
receptor agonist, is tested as a sublingual 1.5 mg tablet
in Phase II clinical trials to evaluate efficacy, safety,
and tolerability in chronic pancreatitis, MS, and AD
patients (Thomson Reuters Pharma, update of June 7,
2012).
Rimonabant (SR-141716A, sanofi, withdrawn
from the market) improved memory in a delayed radial
maze task [450]. Also the development of drinabant
(AVE-1625; Aventis, now sanofi [451]), Org-50189
(Organon, now Merck [452–455]), SLV-330 (Solvay
Pharmaceuticals, now Abbott Laboratories [456, 457])
and of TAK-937 (Takeda [458]) was terminated.
1.6. Chemokine receptors
CC chemokine receptor 2 deficiency aggravated
cognitive impairments and amyloid pathology in a
transgenic mouse model of AD [459]. The role
of the CC-chemokine receptor 5 signaling path-
way in cognitive deficits induced by A␤ was
810 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 9. Dopamine receptor modulators.
described [460]. CC chemokine receptor 5 regu-
lated olfactory and social recognition in mice [461].
Fractalkine receptor (CX3CR1) signaling protected
against plaque-independent cognitive deficits in a
mouse model of AD [462].
RAP-310 (RAPID Pharmaceuticals) is a small sta-
bilized receptor active peptide targeting the CCR5
receptor for the potential treatment of AD. Preclin-
ical data demonstrated that the number of activated
microglia within the dentate gyrus and CA3 hippocam-
pal areas were reduced on treatment with RAP-310
compared to lipopolysaccharide-infused rats. Signifi-
cant reduction in the number of hypertrophic astrocytes
and expression of NFκB was also observed on
treatment with RAP-310 (Thomson Reuters Pharma,
update of June 13, 2011). The structure was not com-
municated.
1.7. Dopamine receptors
The dopaminergic enhancement of cognitive func-
tion was discussed in detail [463]. Research in
experimental animals suggested that stimulation of
dopamine D1 receptors in the prefrontal cortex can
ameliorate spatial working memory related cogni-
tive deficits and may even enhance cognitive function
in healthy animals. Prefrontal dopamine had specific
functions in attentional control and working memory,
which was mediated mainly through D1 receptors
[464]. Activation of D1 /D5 dopamine receptors by
the selective agonist SKF-81297 protected neurons
from synapse dysfunction induced by A␤ oligomers
[465]. Low doses of dopamine D2 receptor agonists
such as bromocriptine and pergolide may be able
to enhance working memory and executive functions
[463]. Dopamine D3 receptor antagonism improved
certain cognitive domains [466].
Dexpramipexole (KNS-760704; Knopp Neuro-
sciences and Biogen Idec under license from the
University of Virginia; Fig. 9) is the (R)-enantiomer of
pramipexole with weak affinities to D2 and D3 recep-
tors (IC50 ’s of 1800 nM and 610 nM, respectively). The
compound is in Phase III clinical trials for an oral treat-
ment of amyotrophic lateral sclerosis patients since
March 2011 (n = 804) in the US, Canada, Europe, and
Australia and in Phase II trials for AD (n = 20) in the
US [467–471]. (Thomson Reuters Pharma, update of
June 21, 2012).
Seridopidine (ACR-343; A. Carlsson Research AB,
now NeuroSearch, Fig. 9) is a dopaminergic stabi-
lizer for the potential oral treatment of Parkinson’s
disease and schizophrenia. A Swedish Phase I trial
began in December 2007. The planned Phase II study
was delayed due to additional toxicological examina-
tions of a metabolite. In the Thomson Reuters Pharma
update of June 25, 2012 the drug is reported to be
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
suspended in favor of the Phase III compound pridopi-
dine (ARC16; Fig. 9) for the treatment of Huntington’s
disease [472–474]).
PF-03800130 (Pfizer, Fig. 9) is a dopamine D2 and
a 5-HT1A partial agonist, a potent 5-HT2B antagonist
and a moderately potent serotonin re-uptake inhibitor
for the potential treatment of manic and depressive
symptoms in bipolar disorder and schizophrenia in pre-
clinical evaluation [475] (Thomson Reuters Pharma,
update of May 23, 2011).
A dual D2 receptor agonist and histamine H3
receptor antagonist is investigated by Angita Phar-
maceuticals for the potential treatment of Parkinson’s
disease (Thomson Reuters Pharma, update of May 9,
2012).
A dual N-acetyltransferase re-uptake inhibitor
and histamine H3 receptor antagonist is investi-
gated by Angita Pharmaceuticals for the potential
treatment of cognitive disorders (Thomson Reuters
Pharma, update of May 10, 2012).
The development of many dopamine receptor lig-
ands was terminated, i.e., of A-412997 (Abbott; a D4
receptor agonist [476–478]), adrogolide (ABT-431,
DAS-431, Abbott Laboratories and Drug Abuse Sci-
ences, a dopamine D1 receptor agonist for the potential
treatment of cocaine addiction and cognitive disorders
[479–481]), dihydrexidine (DAR-0100; DarPharma
under license from Purdue University, a dopamine
D1 receptor agonist [482–486]), dinapsoline (DAR-
201; DarPharma; a dopamine D1 agonist [487–489]),
PRX-5007 (Proximagen; a D1 dopamine receptor
agonist), RGH-1756 (Gedeon Richter, a dopamine
D3 receptor antagonist [490]), S-33138 (Servier; a
D3 receptor antagonist), SB-277011-A (GSK; a D3
dopamine receptor antagonist [491–493]), serido-
pidine (A. Carlsson Research, now NeuroSearch;
a dopaminergic stabilizer) and of TOFA (MCP
Hahnemann University, formerly Allegheny Univer-
sity of Health Sciences, a dopamine D1 receptor
modulator).
1.8. Endothelin receptors
Endothelin-1 is elevated in AD and upregulated by
A␤. Endothelin-A receptor antagonists prevented A␤-
induced increase in ETA receptor expression, oxidative
stress, and cognitive impairment [494]. These findings
provide evidence of overactivity of the endothelin sys-
tem in AD supporting the suggestion that endothelin
receptor antagonists may be of value for the treatment
of this disease [495, 496]. Reduction of endothelin
levels may lead to an improved brain perfusion.
811
ENDG-6010 (EndogenX Inc.) is an endothelin
receptor antagonist for the potential treatment of AD
and dementia including vascular dementia in pre-
clinical evaluation (Thomson Reuters Pharma, update
of November 22, 2011). The structure was not
communicated.
The development of S-0139 (SB-737004; Shionogi),
an endothelin-A antagonist, was terminated [497–
499].
1.9. Estrogen receptors
A number of clinical studies have suggested
that estrogen therapy may delay the onset or con-
tribute to the prevention and/or attenuation of AD
[500–503]. Several comprehensive reviews were
published [504–506]).
The results of the Women’s Health Initiative, a large,
prospective study in which 16,608 post-menopausal
women were randomized to receive either conjugated
equine estrogen (0.625 mg per day) plus medroxypro-
gesterone (2.5 mg per day) or placebo clearly indicated
that, after a mean of 5.2 years of follow-up, the use
of oral conjugated estrogen and medroxyprogesterone
not only did not reduce the risk of heart disease, but led
to a 29% increase in the risk of non-fatal myocardial
infarction and heart disease death, a 41% increase in the
risk of stroke, a 111% increase in the risk of venous
thromboembolism and a 26% increase in the risk of
breast cancer compared with placebo-treated subjects
[507]. Data from the Women’s Health Initiative Mem-
ory Study indicate that treatment with estrogens either
alone or in combination with progestin failed to prevent
age-related memory decline and dementia [508–511].
A follow-up Women’s Health Initiative study on cog-
nitive aging reported that treatment impaired verbal
memory [512–515]. In the MIRAGE study a significant
protective effect was observed only in the youngest
age group studied (i.e., the 50–63 years old age group)
[516]. The Kronos Early Estrogen Prevention Study
was a five year study initiated in 2005 to re-examine
estrogen beneficial effects when initiated at the begin-
ning of the menopause [517]. There may be a “critical
period” around the time of menopause during which
the prescription of estrogen therapy may reduce the
risk of developing AD in later life. This effect may be
most significant in women under 49 years. Prescrip-
tion of estrogen therapy after this point may have a
neutral or negative effect, particularly when initiated
in women over 60–65 years [518, 519].
Despite the controversial clinical reports, many
interesting preclinical papers appeared on the effects
812 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 10. Drugs interacting with estrogen and androgen receptors.
of estrogen on markers of AD. Estrogen stimulated
degradation of A␤ peptide by upregulating neprilysin
[520]. 17␤-estradiol increased intracellular trafficking
of A␤PP and hence reduced maximal A␤ generation
within the trans-Golgi network [521]. The fundamen-
tal mediator of the neuroprotective effects of estrogen
seems to be seladin-1 (the selective AD indicator-1
[522]; for a commentary see [523]). Estrogen protected
from A␤ neurotoxicity by restoring integrin expression
and cell cycle control [524].
Phyto-beta-SERM (University of Southern Cal-
ifornia) is an estrogen receptor beta selective
phytoestrogenic formulation comprised of three phyto-
estrogens for the potential treatment of AD. By
July 2011 Phase I/II studies were ongoing (Thomson
Reuters Pharma, update of August 4, 2011).
Despite big efforts the work on selective estrogen
receptor modulators (SERMs), NeuroSERMs [525]
and on selective estrogen receptor-␤ agonists did not
produce useful cognitive enhancers for clinical devel-
opment. It appears that AstraZeneca, Bayer-Schering,
Celera, Celgene, GSK, J&J, Lilly, Merck-Organon,
Novartis, QuatRx Pharmaceuticals, sanofi, and SRI
International have all terminated their programs on
SERMs. Only ACADIA Pharmaceuticals has a SERM
program ongoing (Thomson Reuters Pharma, update
of March 6, 2012).
A highly selective estrogen receptor-␤ agonist
was discovered by investigating traditional Chinese
medicine in the roots of Glycyrrhizae uralensis Fisch,
i.e., liquiritigenin (7,4 -dihydroxy-flavanone; Fig. 10)
[526]. Liquiritigenin was able to attenuate A␤25-35
induced impairment of learning in rats [527]. Bionovo
is developing MF-101 (Menopause Formula-101,
Menerba), a plant-derived mixture that interacts with
the estrogen receptor-␤ as agonist and contains liquir-
itigenin in Phase II clinical trials (Thomson Reuters
Pharma, update of April 2, 2012).
(–)-Epigallocatechin-3-gallate (EGCG; Fig. 10)
present in green tea acts as an estrogen receptor-␣
(ER-␣) agonist setting in motion receptor tyro-
sine phosphorylation of the p85 regulatory subunit
of PI3K. Subsequently PIP2 is converted to PIP3 ,
which activates Akt. Akt interacts with A␤PP by
phosphorylating C-terminal tyrosine sites. Interaction
with ADAM10 favors the promotion of the non-
amyloidogenic ␣-secretase processing of A␤PP [528,
529]. EGCG reduced A␤-mediated cognitive impair-
ment presumably via flavonoid-mediated presenilin-1
phosphorylation, which reduced AD A␤ production
[530–532]. EGCG prevented lipopolysaccharide-
induced elevation of A␤ generation [533]. The cell
signaling pathways and iron chelation were described
[534–540]. Also ERK and NFκB pathways are
involved [533]. A special formulation of EGCG in
nanolipidic particles to improve its bioavailability was
presented [541].
Neurocrine tested the androgen receptor agonist
dehydroepiandrosterone (DHEA; Fidelin; Fig. 10)
in Phase II/III double-blind, placebo-controlled, clin-
ical trials in Canada, New Zealand, Australia, South
Africa, and Europe. In one center, DHEA was given
to 58 subjects with AD in a 6 month treatment (50 mg
p.o. twice a day) versus placebo. DHEA did not sig-
nificantly improve cognitive performance or overall
rating of change in severity in this study [542]. Part
of DHEA’s pharmacology may also be due to its inter-
action with sigma-1 receptors [543].
The development of E2-CDS (estradiol-chemical
delivery system; Pharmos under license from the
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 11. Merck’s inverse agonists at ␣5␤␥2 GABAA receptors.
University of Florida and IVAX), of MX-4509 and
MX-4565 (MIGENIX, formerly Micrologix, formerly
MitoKor), non-feminizing estrogen derivatives and of
Neurosterol (Endocon) was terminated.
1.10. GABA receptors
1.10.1. GABAA receptors
Many studies describe that inverse agonists of
␣5␤␥2 GABAA receptors, particularly abundant in the
hippocampus, display valuable cognition enhancing
properties (in chronological order) [544–555].
Big efforts have been made particularly by scien-
tists at Merck UK during many years to produce first
L-655,708 (Fig. 11) [556, 557] followed by ␣5IA
(Fig. 11), which was converted in vivo to a highly insol-
uble hydroxymethyl isoxazole metabolite [558–561].
␣5IA restored cognitive deficits in Down syndrome
mice [562, 563]). MK-016 (Fig. 11) was well toler-
ated in young, but not in elderly volunteers [564]. For
excellent medicinal chemistry see [565, 566].
RG-1662 (Roche), a small-molecule ␣5 GABAA
inverse agonist and negative allosteric modulator
(NAM), is evaluated in a multicenter, randomized,
double-blind, placebo-controlled, multiple dose, Phase
I study in Down syndrome patients (n = 33) in the US
813
to assess the safety and tolerability of RG-1662 since
September 2011 (Thomson Reuters Pharma, update of
April 18, 2012). Its structure was not disclosed.
There are many ␣5 GABAA receptor inverse ago-
nists or NAMs in preclinical evaluation (in alphabetical
order):
AC-4402 (Dainippon Sumitomo Pharma) is a par-
tial inverse GABAA receptor agonist for the potential
treatment of AD. Its structure was not communicated
(Thomson Reuters Pharma, update of December 6,
2011).
C-21191 (CoNCERT Pharmaceuticals) is a deuter-
ated ␣5 GABAA receptor inverse agonist derived from
Merck’s L-838,417 (Fig. 11), which was considered
to have an unsuitable pharmacokinetic profile. The
deuterated derivative showed good metabolic stabil-
ity [567] (Thomson Reuters Pharma, update of March
6, 2012).
GABAA receptor ␣5 inverse agonists are explored
at AgeneBio (Thomson Reuters Pharma, update
of December 29, 2010). The structures were not
disclosed.
GABAA receptor ␣5 subtype selective antag-
onists are investigated jointly by scientists of the
University of Wisconsin at Milwaukee and of MSD
for the potential treatment of anxiety, amnesia, and
814 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 12. GABAA receptor antagonists.
alcoholism. The lead compound XLi-093 is a dimer of
imidazo-benzodiazepines (Fig. 12) [568, 569] (Thom-
son Reuters Pharma, update of July 12, 2011).
Medicinal chemists at Kyowa Hakko Kirin pro-
duced the pyrido[2,3-d]pyrimidine-4-one derivative
(Fig. 12) [570]. It appears that the development was
terminated.
RO4938581 (Roche; Fig. 12) and the dichloro-
analogue RO4882224 (Fig. 12) are inverse agonists
at ␣5␤␥2 GABAA receptors [571–575].
UC-1011 (Umecrine; Fig. 12) is a GABAA receptor
antagonist with neurosteroid structure for the treat-
ment of memory and learning disturbances associated
with AD [576] (Thomson Reuters Pharma, update of
January 31, 2012).
The development of FG-8094 (Ferrosan), HT-
2678 (Helicon Therapeutics), radequinil (AC-3933;
AVE-3933, SX-3933; Dainippon Sumitomo [577]),
RU-33965 (Roussel-Uclaf, now sanofi [578–580]), S-
135 (Shionogi [581]), S-8510 (SB-737552; Shionogi
and GSK [582–584], SAR-501788 (sanofi), of sar-
mazenil (Roche [585]), suritozole (MDL-26479;
Hoechst Marion Roussel, now sanofi [586–590]) and
of ZK-91296 and ZK-93426 (Bayer Schering Pharma
[591–594]) was terminated.
1.10.2. GABAB receptors
GABAB receptor antagonists proved to be valuable
cognitive enhancers as was shown in many animal
experiments and in two clinical trials (vide infra).
It is still unclear which GABAB1 receptor isoforms
contribute to cognitive processes. Both GABAB1a
(–/–) and GABAB1b (–/–) mice were impaired rela-
tive to wildtype controls in a continuous spontaneous
alternation behavior test of working spatial memory.
GABAB1a (–/–) mice were impaired in familiar and
novel object recognition tests, but neither GABAB1a
(–/–) nor GABAB1b (–/–) mice were deficient in a
passive avoidance task [595].
CGP36742 (SGS742; Saegis Pharmaceuticals
under license from Ciba-Geigy, now Novartis; Fig. 13)
showed pronounced cognition enhancing properties in
mice, in young and old rats, and in Rhesus monkeys
[596–600]). It was taken into two Phase II clini-
cal trials, first in patients with MCI and in mild
to moderate AD patients. It significantly improved
attention and working memory in MCI and patients
with mild AD, but not in patients with moder-
ate AD [601, 602]. CGP36742 was characterized in
binding and electrophysiological experiments [603].
Repeated administration of CGP36742 upregulated
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 13. GABAB receptor antagonists.
GABAB receptor binding sites in cortex and spinal
cord [604–606], which may be predictive of poten-
tial antidepressant effects according to a hypothesis
first presented in 1984 [607]. CGP36742 enhanced the
release of somatostatin [608–611]. Single administra-
tion of CGP36742 enhanced the levels of both mRNA
and protein of nerve growth factor and brain-derived
neurotrophic factor (BDNF) in brain and spinal cord
of rats [612]. Administration of CGP36742 (SGS742)
reduced the levels of CREB2 in the hippocampi of rats
[613]. It was shown that the effects of CGP36742 were
strain dependent in mice [614, 615]. Major signaling
cascades were not involved in the memory enhancing
effects of CGP36742 [616], but phosphorylated protein
kinase A and synapsin isoform levels were linked to
spatial memory enhancement [617, 618]. CGP36742
also antagonized actions of ␥-hydroxybutyrate [619,
620]. Special GC-MS methodology was required to
determine plasma and brain levels of CGP36742 [621,
622]. CGP36742 was also able to suppress spike
and wave discharges in an animal model of absence
epilepsy (GAERS, genetic absence epilepsy rats of
Strasbourg [623–627]).
CGP36742 and CGP51176 (AVE-7398; Ciba-
Geigy, now Novartis outlicensed to Aventis, now
sanofi; Fig. 13) showed pronounced antidepressant
properties in several animal experiments [628–631],
which may be due to the enhanced release of BDNF
[612] and/or to the upregulation of GABAB receptor
binding sites [604, 632]. Three reviews were published
[633–635].
The high affinity GABAB receptor antagonists
CGP56433 and CGP63360 (Fig. 13) improved
815
learning and memory in active and passive avoidance
tests in mice and rats at low doses of 0.1 mg/kg p.o.
[624, 636, 637].
PAMs of GABAB receptors are currently investi-
gated at Addex Therapeutics, at Hoffmann-La Roche,
and at AstraZeneca. For a patent survey on novel
GABAB receptor positive modulators, see [638]. The
Addex compounds ADX-1a, ADX-1b, ADX-71441,
and ADX-18200 were characterized in animal mod-
els of pain, fragile X syndrome, urinary incontinence,
and gastroesophageal reflux disease (Thomson Reuters
Pharma, update of June 19, 2012). Structures were not
communicated.
1.10.3. GABAC receptors
Researchers of the University of Sydney presented
the first selective and brain penetrating GABAC recep-
tor antagonists (R)-ACBPA and (S)-ACBPA (Fig. 14).
(S)-(3-amino-cyclopentenyl)-n-butyl-phosphinic acid
had a higher affinity to ρ1 receptors (Kb = 5 ␮M for
ρ1 and 11 ␮M for ρ2 receptors). The (R)-(enantiomer
showed a higher affinity for ρ2 receptors (Kb = 60 ␮M
for ρ1 and 6 ␮M for ρ2 receptors). Both compounds
showed dose dependent learning and memory enhanc-
ing effects in an object recognition test in mice at
doses of 10 and 100 mg/kg i.p. [639, 640]. One of
the compounds will be developed by NeuroTherapeu-
tics (Thomson Reuters Pharma, update of January 24,
2012). Novel cyclic phosphinic acids as GABAC recep-
tor antagonists were discovered [641]. Two reviews
on the medicinal chemistry of GABAC receptors were
published [642, 643].
816 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 14. Two GABAC receptor and a galanine-3 receptor antagonist.
GABAC receptor antagonists are also evaluated
for the potential treatment of vascular eye disease at
Aarhus University (Thomson Reuters Pharma, update
of December 13, 2011).
1.11. Galanin receptors
Galanin and galanin receptors are overexpressed
in limbic brain regions associated with cognition in
AD [644, 645]. Galanin impairs cognitive abilities
in rodents. GAL-R1 receptors play a role in aversive
memories [646–648].
HT-2157 (SNAP-37889; Dart NeuroScience fol-
lowing the acquisition of Helicon Therapeutics
licensed from Lundbeck; Fig. 14) is a galanin-3 recep-
tor antagonist for the treatment of major depressive
and cognitive disorders such as memory loss in Phase
I/II since August 2011 (n = 28) in the US. The study
is estimated to be complete in May 2012 [649–651]
(Thomson Reuters Pharma, update of April 24, 2012).
1.12. Glutamate receptors
1.12.1. AMPA receptors
AMPA receptor stands for ␣-amino-3-hydroxy-5-
methyl-4-isoxazole-propionic acid receptor, which is
a non-NMDA-type ionotropic transmembrane receptor
for glutamate that mediates fast synaptic transmission
in the CNS [652].
1.12.1.1. Piracetam-type compounds. Piracetam
(UCB-6215; Nootropil, UCB; Fig. 15) was discovered
more than forty years ago [653]. For decades it was
considered as “a drug without a mechanism”, i.e., a
“nootropic agent” [1, 2]. Now it is firmly established
that piracetam acts as a weak positive modulator of
AMPA receptors. The X-ray structure of piracetam
binding to the S1S2 dimer interface of GluA2 is
available [654]. Piracetam can occupy three binding
sites, binding site 1 analogous to the binding of
aniracetam, binding site 2 analogous to the binding of
cyclothiazide, and a unique new binding site 3. An
X-ray structure was also obtained for GluA3i in the
presence of piracetam. The density in binding site 3
was not as strong as in GluA2. The orientation within
this binding site is identical to that of GluA2o and
GluA2i . For the alternative splicing into flip and flop
versions of AMPA receptors, see [655].
A comprehensive review of the pharmacological
properties and the clinical uses of piracetam was pre-
sented [656] as was an overview on piracetam and
piracetam-like drugs [657].
Oxiracetam (SF-2522; Neuromet, ISF, GSK)
was launched in 1987, Aniracetam (Ro-13-5057;
Draganon, Sarpul; Roche, Toyama) in 1993 [658], and
Pramiracetam (CI-879; Neupramir; Pfizer, Lusofar-
maco, all Fig. 15) in 1993.
Dimiracetam (NT-11624; BND-11624; Neurotune,
Brane Discovery, Fig. 15) is in Phase II clinical tri-
als for the treatment of HIV-associated pain in South
Africa. In October 2010 results from 111 patients
showed the drug was safe and well tolerated and all sub-
jects had a significant improvement in pain symptoms.
For medicinal chemistry, see [659, 660] (Thomson
Reuters Pharma, update of May 4, 2012).
NT-24336 (NiK-13317; Neurotune, Brane Discov-
ery after its spin-off from Nikem Research) is the
N-p-tolyl derivative of dimiracetam in preclinical eval-
uation for the treatment of diabetic neuropathy and
neuropathic pain (Thomson Reuters Pharma, update
of September 26, 2011).
Nefiracetam (DM-9384; Motiva; Translon; Neuren
Pharmaceuticals under license from Daiichi Sankyo,
Fig. 15) is in Phase II clinical trials for the treat-
ment of neuropsychiatric complications in post-stroke,
traumatic brain injury, AD, and Parkinson’s disease
patients [661–663]. The drug activated PKA and PKC
with subsequent phosphorylation of nAChRs [664,
665] (Thomson Reuters Pharma, update of May 30,
2012).
The development of many piracetam-type com-
pounds was terminated, i.e., of alaptide (VUFB
[666, 667]), cebaracetam (Ciba-Geigy, now Novartis
[668]), CI-933 (Parke-Davis, now Pfizer), (–)-
clausenamide (Chinese Academy of Medical Sciences
[669, 670]), fasoracetam (NS-105; LAM-105; Nip-
pon Shinyaku [671, 672]), nebracetam (WEB 181
FU; Boehringer Ingelheim [673–675]), rolziracetam
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 15. Piracetam and piracetam analogues.
(CI-911; Pfizer; [676, 677]), and of the cognitive
enhancers from the University of Florence unifi-
ram (DM-232), sunifiram (DM-235 [678–681]), and
sapunifiram (MN19 [682–684]).
1.12.1.2. AMPAkines. The first observations of the
pharmacological potentiation of AMPA receptors were
made via electro-physiological recordings using the
nootropic drug aniracetam (Fig. 15) [685–687]. The
groups of Gary Lynch of the University of California
at Irvine and of Gary A. Rogers of the University of
California at Santa Barbara presented the first benza-
mide drug 1-BCP (BA-14, Fig. 16) [688, 689]. The
drug crossed the blood-brain barrier and reversibly
increased the amplitude and prolonged the duration
of field excitatory postsynaptic potentials. Evidence
for improved memory was shown in the Morris water
maze and in a radial maze.
Later it was found that AMPAkines enhanced synap-
tic transmission, lowered the threshold, and increased
the magnitude of long term potentiation and increased
the release of BDNF [690–692]).
The prototypic AMPAkine CX-516 (BDP-12,
BA-74; Ampalex, SPD-420, Org-24292; Cortex Phar-
maceuticals; Fig. 16) was tested in several clinical trials
in AD and MCI, in schizophrenia, ADHD, sleep disor-
ders, fragile X syndrome, and autism. The development
of Ampalex was terminated in December 2006.
817
CX-516 binds to a different site than other mod-
ulators [693]. The compound has been characterized
as a type II AMPAkine, as the more potent CX-691
(farampator). Type I AMPAkines slow the channel
closing by factors up to 50, whereas type II APAkines
accelerate the channel opening by factors up to
three.
CX-717 (Cortex) is an AMPAkine for the potential
treatment of ADHD, AD, and respiratory disorders in
Phase II clinical trials. It is also evaluated to allevi-
ate the effects of sleep deprivation [694]. Oral and i.v.
formulations are evaluated (Thomson Reuters Pharma,
update of May 16, 2012). The structure was not
communicated.
CX-1739 (Cortex) is a potential follow-up com-
pound of CX-717 for the potential treatment of sleep
apnea and neurological diseases including ADHD
and AD. Phase II results of a sleep apnea trial have
been reported in February 2011. Cortex is evaluat-
ing oral and injectable formulations (Thomson Reuters
Pharma, update of May 16, 2012). The structure was
not communicated.
S-47445 (CX-1632; Servier under license from Cor-
tex Pharmaceuticals) is an AMPAkine for the potential
treatment of memory and cognitive impairments asso-
ciated with neurodegenerative disease including AD.
A Phase I trial has been completed by Servier in
October 2011 (Thomson Reuters Pharma, update of
818 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 16. AMPAkines of the benzamide type.
April 2, 2012). The structure of S-47445 was not
communicated.
CX-546 (Fig. 16) promoted enhancement of glucose
utilization by cortical, hippocampal, and cerebel-
lar astrocytes [695]. CX-546 significantly prolonged
synaptic responses in CA1 pyramidal cells, but at the
same concentrations had only weak modulatory effects
in reticular thalamic nucleus neurons [696].
CX-554 (BDP-20; Fig. 16) was useful to eluci-
date the multiple modulatory sites of AMPA receptors
[697]. It was approximately ten-fold more potent than
CX-516 (BDP-12) in behavioral effects [698] and was
more potent in enhancing feedforward than feedback
inhibition [699].
The co-crystal structures of the AMPA receptor
GluA2 S1S2 ligand-binding domain in complex with
aniracetam (Fig. 8) and with CX-614 (Fig. 9) were pre-
sented [700]. Both potentiators bind within the dimer
interface adjacent to the hinge in the ligand-binding
core clamshell.
Farampator (CX-691; ORG-24481; SCH-900460;
Fig. 16) was developed jointly by Cortex and Schering-
Plough (formerly Organon; now Merck), but the
development was terminated due to concerns about car-
diac safety. Farampator enhanced cognitive effects in
rats [701].
Cortex is developing several other AMPAkines,
whose structures were not disclosed, such as CX-1942,
CX-2007, and CX-2076 (Thomson Reuters Pharma,
update of May 16, 2012).
New benzoxazinone scaffolds with very high
potency were published recently. The readout is the
EC2x value, the concentration of the compound, which
when perfused onto cultured rat embryonic hippocam-
pal neurons doubled the steady-state current induced
by 500 ␮M glutamate. CX-614 had an EC2x of 2.3 ␮M,
compound 4 (Fig. 16) an EC2x of 0.06 ␮M and
compound 11r (Fig. 17) an EC2x of 0.7 nM, a big
improvement over the 5 mM value of aniracetam [702,
703]. Potent AMPAkines with benzotriazinone, benzo-
bistriazinone, and benzopyrimidinone structures were
also disclosed [704, 705].
Excellent reviews on AMPA potentiators have been
published [706–711].
The development of CX-929, CX-1501, CX-1796,
and CX-1837 (Cortex Pharmaceuticals), Org-26576
(Organon, now Merck [712–716]), and of S-70340
(Servier) was terminated.
1.12.1.3. Biarylpropylsulfonamides. PF-04958242
(Pfizer; Fig. 17) is an AMPA receptor potentiator
for the potential treatment of CDS in Phase I trials
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 17. AMPAkines of the biarylpropylsulfonamide type and novel modulators of AMPA receptor deactivation and desensitization.
in healthy volunteers (n = 24) since August 2010. In
addition, a clinical study (NCT01518920) is underway
to evaluate the effects of PF-049582432 in subjects
with age-related hearing loss (n = 42) in the US [717]
(Thomson Reuters Pharma, update of May 11, 2012).
LY-392098 (Eli Lilly; Fig. 10), LY-404187 (Fig. 17),
and it (R)-enantiomer LY-4516146 have been thor-
oughly investigated in preclinical models as novel
antidepressants [718–733].
LY-404187 and LY-503430 (Fig. 17) have been
characterized in rodent models of Parkinson’s disease
[734–738]. LY-404187 and mibampator (LY-451395)
reversed the central effects of acutely intoxicating
doses of ethanol in rats [739].
In continuation of their work, Lilly scientists have
thoroughly analyzed the properties of two novel PAMs
of GluA2 desensitization and deactivation, i.e., com-
pounds CMPDA and CMPDB (Fig. 17) with EC50 ’s
of 45 nM at GluA2i receptors and 63 nM at GluA2o
receptors for CMPDA and EC50 ’s of 122 nM at
GluA2i and 470 nM at GluA2o receptors for CMPDB,
respectively [740]. CMPDB attenuated the rate of
deactivation for GluA2i and GluA2o receptors by fac-
tors of 7 and 5-fold, respectively. CMPDA slowed the
819
rate of deactivation of GluA2o receptors by 2-fold, but
had no effect on GluA2i receptor deactivation.
Scientists of GSK (Harlow) discovered novel AMPA
receptor modulators, compound 17i (Fig. 18) [741]
and compound 9a (Fig. 18) [742]. The challenges for
and the current status of research of positive modula-
tors of AMPA receptors were discussed [743, 744].
A HTS hit was optimized to a potent AMPA recep-
tor modulator at Merck UK [745]. Compound 5
(Fig. 18) had good bioavailability [746]. Compound
19 (Fig. 18) displayed high aqueous solubility and
excellent stability in microsomal and hepatocyte prepa-
rations [747]. For reviews describing the state of the
art in 2000 and in 2010, see [748, 749].
The AMPA receptor potentiator PF-04778574 of
Pfizer (Fig. 18) is a potential follow-up compound of
PF-04958242 for the treatment of CDS [750].
(R,R)-PIMSD (University of Copenhagen, Fig. 18)
is a dimeric positive modulator bridging two identical
AMPA receptor binding sites [751]. PIMSD showed
cognitive enhancing effects on place learning in mice
[752].
The development of mibampator (LY-451395; Eli
Lilly) [753, 754]) and of LY-450108 was terminated.
820 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 18. Positive allosteric modulators of AMPA receptors.
1.12.1.4. Benzothiadiazides. Cyclothiazide (Fig. 19)
is a diuretic and antihypertensive drug launched by
Lilly in 1963. In 1993 it was discovered that it acts
as a PAM of AMPA receptors [755]. In 2003 it was
recognized that it acts as a NAM of GABAA recep-
tors [756, 757]. In 2007 it was found that it acts as a
NAM of mGluR1 receptors [758]. In 2008 it was dis-
covered that it acts as a NAM of GABAC receptors
[759]. Note that cyclothiazide contains 4 asymmetric
centers theoretically giving rise to 16 stereoisomers,
which is reduced to 8 due to the geometrical restriction
of the methylene bridge. The four diasteromeric race-
mates have been separated by chromatography. The
most potent fraction was resolved further into the two
enantiomers by chiral HPLC showing a five times more
potent effect in potentiating AMPA transmission than
the cyclothiazide mixture [760].
Cyclothiazide eliminated desensitization of GluA2i
receptors and significantly slowed the rate of desen-
sitization of GluA2o receptors, but had no effect on
deactivation on either GluA2i or GluA2o receptors.
Cyclothiazide alters the channel gating events [761,
762].
IDRA-21 (Fidia-Georgetown Institute for the Neu-
rosciences; Fig. 19) crossed the blood-brain barrier
readily and improved alprazolam-induced learn-
ing deficits in rats and monkeys [763–765]. Oral
administration of IDRA-21 significantly improved per-
formance in a delayed non-matching-to-sample task
in young macaques [766]. Racemic IDRA-21 was
resolved into the two enantiomers [767]. A signifi-
cant increase in drug affinity was achieved by alkyl
substitution at the 5 -position [768].
S-18986 (Servier, Fig. 19) was in Phase II clini-
cal trials, but its development was terminated due to
rare side effects. Its pharmacology was extensively
documented [769–774]. For an elegant asymmetric
synthesis see [775]. The development of BIIR-777
(Boehringer-Ingelheim, Fig. 19) was also terminated.
1.12.1.5. 1-Hydroxyazoles. Novo Nordisk was inves-
tigating a series of 1-hydroxyazoles (Fig. 19) as AMPA
receptor agonists for the potential treatment of AD. The
development activities were suspended [776].
1.12.2. NMDA receptors
N-methyl-D-aspartate is the selective agonist, which
binds to this specific type of ionotropic glutamate
receptors [777].
A substantial progress in the treatment of patients
suffering from AD was achieved with the launch
of the NMDA receptor channel blocker memantine
(Axura, Ebixa, Namenda, Memary; Merz; Fig. 20).
The compound was launched by Merz in Germany in
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 19. Benzothiadiazides and 1-hydroxy-azole.
Fig. 20. Two NMDA receptor antagonists.
1982 for various neurological syndromes and cogni-
tive dysfunction [778], by Lundbeck in the EU for the
treatment of moderate to severe AD in November 2002,
by Forest Laboratories in the US in January 2004, and
by Daiichi Sankyo in Japan in June 2011. Sales for
Namenda by Forest in 2011 were USD 1,400 million,
sales for Ebixa by Lundbeck in 2011 were USD 514
million and sales for Daiichi Sankyo in 2011 were USD
123.5 million (Thomson Reuters Pharma, update of
June 29, 2012).
There are currently 1960 papers on memantine
listed in PubMed (as of May 28, 2012). Memantine
is a moderate affinity, voltage-dependent, uncompeti-
tive channel blocking NMDA receptor antagonist first
synthesized at Lilly and patented in 1968 [779]. It
inhibited NMDA receptors at near resting potential
with an approximate affinity of 1 ␮M and blocked
821
NR2A, NR2B, NR2C, and NR2D receptors expressed
in Xenopus oocytes with IC50 ’s of 0.89, 0.40, 0.32, and
0.28 ␮M, respectively [780]. It displaced [3 H]MK-801
from binding to postmortem human brain with a Ki
of 0.54 ␮M [781]. Memantine blocked NMDA chan-
nels activated by high concentrations of L-glutamate
at −70 mV with a Kon of 2 to 4 × 105 M−1 s−1 and
a Koff of around 0.2 s−1 [780]. Memantine binds to at
least two sites within the NMDA receptor channel, a
shallow and a deep site [782]. Memantine also binds to
␣4␤2 nAChRs with an IC50 of 6.6 ␮M, to ␣7 nAChRs
with an IC50 of 0.33 ␮M to 1.68 ␮M [780] and to 5-
HT3 receptors with an IC50 of 2.3 ␮M. Serum levels of
memantine in humans with the usual daily maintenance
dose of 20 mg are within the range of 0.5 to 1.0 ␮M
[783]. Physiologically NMDA receptors are transiently
activated by mM concentrations of L-glutamate in the
synapse following strong depolarization of the postsy-
naptic membrane from a resting potential of −70 mV
to a value of −20 mV, which rapidly relieves their
voltage-dependent blockade by Mg2+ ions. The com-
bination of fast-offset kinetics and relatively strong
voltage-dependency allows memantine to rapidly leave
the NMDA channel upon transient physiological acti-
vation by mM concentrations of synaptic glutamate.
Under pathological conditions in AD, NMDA recep-
tors are activated by ␮M concentrations of glutamate
for much longer periods of time leading to a moderate
prolonged depolarization of about −50 mV. Meman-
tine can block this sustained tonic activation in contrast
to Mg2+ ions. Thus memantine can differentiate
822 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
between low-level pathological activation of NMDA
receptors in AD (“noise”) and physiological synaptic
NMDA receptor activation (“signal”; “signal to noise
hypothesis”) [780].
In addition memantine displayed disease-modifying
effects on hallmarks of AD. Memantine significantly
reduced the levels of insoluble A␤, of A␤ dodecamers
(A␤*56), prefibrillar soluble oligomers, and fibrillar
oligomers in triple transgenic AD mice of 6, 9, and 15
months of age [784]. Memantine lowered A␤ peptide
levels in neuronal cultures and in A␤PP/PS1 trans-
genic mice [785]. Memantine treatment significantly
reduced the amount of phosphorylated tau (at Thr181)
in the CSF of 13 AD patients treated for one year with
20 mg memantine daily (p = 0.018) [786].
A combination treatment of donepezil and meman-
tine showed synergistic effects in a test for spatial
learning and recall in a transgenic mouse model of AD
[787].
For further reviews on primarily biological and
mechanistic data, see [788–791].
Clinical trials were initiated by the medical team
of Merz under Hans Jörg Möbius, who collaborated
with many outstanding clinicians. The results of the
clinical trials are described in the listed papers [778,
792–829] as were the effects of memantine for the
treatment of dementia in adults with Down syndrome
from the MEADOWS study [830]. Memantine was
also prescribed for the neuroenhancement of healthy
individuals [831].
A review on safety and efficacy was published [832]
as were pharmacoeconomic reviews [833–836].
Merz and Forest developed memantine extended
release (memantine ER; Namenda XR), a once-
daily 28 mg extended-release formulation, which was
approved by the FDA in June 2010. The formulation
was registered (Thomson Reuters Pharma, update of
June 18, 2012).
Adamas Pharmaceuticals is developing a meman-
tine + donepezil fixed dose combination as an
extended release formulation. Phase I clinical trials
have been completed by March 2011. In May 2012, the
FDA approved to conduct Phase III studies in an end-
of-Phase II meeting. The company planned to initiate
a pivotal Phase III safety study in patients (expected
n = 300) with AD (Thomson Reuters Pharma, update
of May 16, 2012). For a pharmacoeconomic evaluation
of the donepezil and memantine combination [834].
Neramexane (MRZ-2/579; Merz; Fig. 20) is cur-
rently in Phase III clinical trials for the treatment of
tinnitus. Japanese licensee Kyorin is codeveloping the
drug in Japan. Clinical studies for the indication AD
were terminated in October 2008 (Thomson Reuters
Pharma, update of June 22, 2012). For the preclinical
characterization, see [837, 838].
EVT-103 (ENS-103; Evotec under exclusive license
from Roche) is an orally active NMDA NR2B sub-
type specific antagonist for the potential treatment
of treatment-resistant depression and AD in Phase II
development for both indications (Thomson Reuters
Pharma, update of May 25, 2012). The structure was
not communicated.
Mnemosyne is investigating small molecule NR2B
allosteric modulators to improve cognitive dysfunction
in AD (Thomson Reuters Pharma, update of Febru-
ary 17, 2012). The structures were not communicated.
Also selective NR2A and NR2D allosteric modulators
are evaluated for the potential treatment of ADHD,
autism, and stroke (Thomson Reuters Pharma, update
of February 29, 2012 and Nov. 22, 2011, respectively).
NRX-1059 (Naurex) is the lead from a series of
NMDA receptor agonists for the potential i.v. treatment
of schizophrenia. A second series of partial NMDA
receptor agonists are compounds coded NRX-20xx
(Thomson Reuters Pharma, updates of June 11 and
June 12, 2012, respectively). The structures were not
communicated.
The development of CR-3394 (Rottapharm Madaus
[839, 840]), CNS-5161 (Paion, formerly Cambridge
NeuroScience), D-cycloserine (a NMDA/glycine
receptor agonist, Searle, now Pfizer [841–846]), DD-
20207 and DD-20197 (DiverDrugs SL), dexanabinol
(HU-211; PA-50211, Sinnabinol; Pharmos, under
license from the Hebrew University of Jerusalem)
was terminated, as was the development of EVT-101
(Evotec, Roche), an orally active NMDA NR2B sub-
type specific antagonist and of NT-13 (a partial agonist
at the NMDA receptor; Naurex, formerly Nyxis Neu-
rotherapeutics).
1.12.3. Metabotropic glutamate receptors
(mGluRs)
For a superb review on all eight mGluRs as novel
drug targets, see [847]. Activation of mGluRs may lead
to a novel approach for the treatment of schizophrenia
[848]. A special issue on mGluRs and cognition was
published in the European Journal of Pharmacology
[849]. Efforts of targeting mGluRs for the treatment
of CDS were presented [850, 851]. One publication
deals with mGluRs as therapeutic targets for cognitive
disorders [852]. Reviews on mGluR2/3, schizophre-
nia, and cognition were presented [853–855]. The
effects of mGluR2/3 agonism and antagonism on
schizophrenia-like cognitive deficits were discussed
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
[856]. mGlu2/mGlu3 double knock-out mice revealed
a role for group II mGluRs in cognition [857]. The
difference of effects of mGlu2/3 and mGlu5 recep-
tor agonists on cognitive impairment was elucidated
[858]. The role of mGlu5 receptors in modulation
of cortical activity and cognition was studied [859].
Activation of type 5 mGluRs attenuated deficits in cog-
nitive flexibility induced by NMDA receptor blockade
[860]. One investigation deals with the role of mGluR5
antagonism in learning and memory [861]. The func-
tional interaction of mGluR5 and NMDA receptor was
elucidated [862]. The role for mGluR5 in successful
cognitive aging of rats was described recently [863].
The role of mGluR7 at the interface of cognition and
emotion was also communicated [864].
ADX-71149 (Janssen Pharmaceuticals, formerly
Ortho-McNeil under license from Addex Therapeu-
tics; Fig. 21) is a PAM of mGluR2 for the treatment
of psychiatric disorders including schizophrenia, anx-
iety, AD, and depression [865, 866]. In March 2011 a
Phase IIa trial was initiated in Europe (n = 105). In June
2012, a multicenter, double-blind, placebo-controlled,
Phase II trial of the drug as an adjunct to antidepressant
treatment was initiated in 94 adult patients with major
depressive disorder who are also suffering from anxi-
ety symptoms in Ukraine, Russia, Romania, Hungary,
and Bulgaria. Subjects would receive oral twice daily
ADX-71149 (25 to 150 mg) as an adjunct to antide-
pressant therapy and the primary endpoint would be
the change from baseline in the Hamilton Anxiety Rat-
ing Scale score (Thomson Reuters Pharma, update of
June 19, 2012).
RG-1578 (R-1578; presumed to be RO-4995819,
Roche) is a small-molecule mGluR2/3 NAM in a
Phase II study in patients with major depressive dis-
orders (n = 480) since December 2011. By February
2012, RG-1578 had shown antidepressant and cogni-
tive enhancing effects in a broad range of preclinical
models (Thomson Reuters Pharma, update of May
22, 2012). The structure of RG-1578 has not been
disclosed.
RG-7090 (RO-4917523; Roche, Fig. 21) is a
mGluR5 antagonist for the potential treatment of
depression and fragile X syndrome in Phase II clin-
ical trials since March 2009, which was completed in
September 2011. In February 2012, recruitment began
for a randomized, double-blind, parallel-group, Phase
II study (n = 315) in the US, Europe, Chile, Mexico,
and Taiwan (Thomson Reuters Pharma, update of June
20, 2012).
BCI-838 (MGS-0210; BrainCells Inc. under license
from Taisho Pharmaceutical; Fig. 21) is a prodrug of
823
BCI-632 (MGS-0039, Fig. 21), a mGluR 2/3 antag-
onist with neurogenesis stimulating properties for
the treatment of CNS disorders including treatment-
resistant depression as well as major depressive
disorder and AD in Phase I clinical trials since Febru-
ary 2012 [867, 868] (Thomson Reuters Pharma, update
of March 19, 2012).
STX-107 (Seaside Therapeutics under license from
Merck; Fig. 21) is a mGluR5 antagonist for the treat-
ment of fragile X syndrome and autism in Phase I trials
since September 2009 [869–876] (Thomson Reuters
Pharma, update of February 9, 2012).
Other cognition enhancing mGluR ligands are in
preclinical evaluation (in alphabetical order):
ADX-63365 (Addex Therapeutics; Fig. 21 shows
the structurally similar compound ADX-50938) is
an orally available PAM of mGluR5 for the poten-
tial treatment of schizophrenia and other indications
involving cognitive impairment [877] (Thomson
Reuters Pharma, update of March 21, 2012). The bio-
logical characterization of a structurally close analogue
ADX-47273 (Fig. 21) was described in great detail
[878].
Addex Therapeutics is investigating a series of
NAMs of mGluR2 for the potential oral treatment
of depression and AD (Thomson Reuters Pharma,
update of June 19, 2012). The structures were not
communicated.
DT-2228 (Domain Therapeutics; Fig. 21) is a
mGluR2 NAM for the potential treatment of AD and
depression [879] (Thomson Reuters Pharma, update
of December 13, 2011). For the original discovery and
the following re-exploration of the PHCCC scaffold,
see [880–882].
Pfizer is investigating mGluR2 PAMs (lead struc-
ture shown in Fig. 21) for the treatment of CNS
disorders [883–885] (Thomson Reuters Pharma,
update of March 24, 2011).
RO-4491533 (Roche; Fig. 21), a mGluR2/3 dual
antagonist, acts as a cognitive enhancer [886–890]
(Thomson Reuters Pharma, update of January 19,
2011).
Roche (under license from Seaside Therapeutics
under license from Vanderbilt Univ., Nashville TN)
is investigating mGluR5 inhibitors for the potential
treatment of fragile X syndrome and autism (Thomson
Reuters Pharma, update of June 20, 2012). Structures
were not communicated.
Sanofi is investigating mGluR2 PAMs for the poten-
tial treatment of CDS (Thomson Reuters Pharma,
update of May 09, 2011). Structures were not
communicated.
824 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

Fig. 21. Metabotropic glutamate receptor ligands.

VU-0430644 (ML-254; Janssen under license from compound showed efficacy in animal models of
Vanderbilt University, Fig. 21) is an mGluR5 PAM cognitive enhancement and was found to effec-
for the potential treatment of schizophrenia. The tively treat the positive symptoms of schizophrenia
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
(Thomson Reuters Pharma, update of April 17,
2012).
The development of ADX-71743 (Addex Therapeu-
tics; a mGluRR7 NAM), CTEP (Roche; a mGluR5
receptor antagonist [891, 892]), LY-181837 and LY-
487379 (Lilly; PAMs of group II mGluRs [893, 894])
and LY-341495 (Lilly, a mGluR2/3 antagonist [895])
was terminated as was MRZ-8676 (Merz, a NAM of
mGlu5 receptors [896]).
1.13. G-protein coupled orphan receptors
The potential of G-protein coupled Orphan Recep-
tors is still largely unexplored.
ESN-502 (Euroscreen) is a G-protein coupled recep-
tor 3 (GPR3) modulator for the potential treatment of
AD (Thomson Reuters Pharma, update of April 30,
2012). The structure was not communicated.
G-protein coupled receptor 3 antagonists (GPR3;
Galapagos) may be of use for the potential treatment
of AD (Thomson Reuters Pharma, update of May 21,
2012). The structures were not communicated.
GPR12, GPR27, GPR31, GPR52, GPR78, GPR-
83, GPR135, GPR139, GPR151, GPR153, and
GPR173 antagonists (Omeros) may be of use for the
potential treatment of cognitive disorders and other
CNS disorders (Thomson Reuters Pharma, update of
May 24, 2012). The structures were not communicated.
Mas-related G-protein coupled receptor antag-
onists (Omeros) are investigated for the potential
treatment of cognitive impairment (Thomson Reuters
Pharma, update of May 24, 2012). The structures were
not communicated.
RGS-14 (University of Malaga) is a protein reg-
ulator of G-protein signaling 14 inhibitor for the
potential treatment of memory loss (Thomson Reuters
Pharma, update of January 10, 2012). The structure
was not communicated. Extensive preclinical investi-
gations were published [897–899].
1.14. Histamine receptors
Memory tests in experimental animals have shown
that in particular histamine H3 receptor antagonists
are valuable cognitive enhancers. Six recent reviews
describe the development of this field in great detail
[900–905].
ABT-288 (Abbott) entered a randomized, double-
blind, placebo-controlled, Phase II clinical study in
patients with schizophrenia (n = 210; NCT01077700)
in April 2010 in the US and a second Phase II study in
825
patients with AD in Russia and the Ukraine (n = 242) in
March 2010 [903] (Thomson Reuters Pharma, update
of May 06, 2011). The structure of ABT-288 was not
disclosed.
AZD-5213 (AstraZeneca) was in Phase I clini-
cal trials in the USA since June 2010 to assess
safety and pharmacokinetics in 88 healthy volunteers
(NCT01548287). In April 2012, a Phase IIa trial to
assess the effect on sleep in patients with AD and MCI
was initiated (Thomson Reuters Pharma update of July
3, 2012). The structure was not disclosed.
JNJ-17216498 (ALZA Corp, a wholly-owned sub-
sidiary of J&J) is an orally active, selective H3 receptor
antagonist for the treatment of narcolepsy in Phase
II clinical trials since December 2006, which were
completed in December 2007 [906] (Thomson Reuters
Pharma, update of March 28, 2011).The structure of
JNJ-17216498 was not disclosed.
S-38093 (Servier) and the related structure S-38471-
1 (Fig. 22) are lead compounds from a series of
histamine H3 antagonists with wakefulness-promoting
and cognitive-enhancing effects. Since July 2011 a
Phase IIb study of S-38093 is underway in 600 mild to
moderate AD patients in Australia, Brazil, Bulgaria,
Chile, the Czech Republic, France, Germany, Hun-
gary, Mexico, Portugal, Romania, Russia, and South
Africa. The trial is expected to complete in April 2014
(Thomson Reuters Pharma, update of September 14,
2011).
SAR-110894 of sanofi is in Phase II clinical trials for
the potential oral treatment of cognitive deficits asso-
ciated with AD, schizophrenia, and attention deficit
disorder patients since February 2011 in the US
(n = 520; NCT01266525; Thomson Reuters Pharma,
update of May 1, 2012). The structure was not dis-
closed.
Irdabisant (CEP-26401; Cephalon, now Teva;
Fig. 22) is a non imidazole containing histamine H3
receptor antagonist in Phase I clinical trials since
March 2010 for treatment of cognition deficits in AD.
In March 2011 good safety data were communicated.
The discovery and characterization was described in all
details [907–915] (Thomson Reuters Pharma, update
of May 29, 2012).
MK-3134 (Merck) is an oral histamine H3 receptor
inverse agonist acting as a cognitive enhancer for the
potential treatment of dementia. Phase I trials were
initiated in June 2007 in the UK (n = 31), in August
2007 in Belgium (n = 32), and in June 2010 in Belgium
(n = 24) in healthy subjects (Thomson Reuters Pharma,
update of January 24, 2011). The structure was not
communicated.
826 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 22. Histamine H3 receptor antagonists or inverse agonists.
PD-9475 (betahistine; P2D Biosciences; Fig. 22)
is an oral formulation of the H3 receptor antagonist
betahistine in a Phase Ib trial since February 2011
for the treatment of ADHD [916] (Thomson Reuters
Pharma, update of April 26, 2012).
There are several histamine H3 receptor antagonists
or inverse agonists in preclinical evaluation (in alpha-
betical order):
Ciproxifan (FUB-359; INSERM; Fig. 22) is a cog-
nition enhancer for the potential treatment of dementia,
schizophrenia, and AD [917–920] (Thomson Reuters
Pharma, update of January 24, 2012).
EVT-501 (EDC-2) and EVT-502 (EDC-3; Evotec)
are small molecule H3 receptor antagonists for the
potential treatment of cognitive and sleep disorders
(Thomson Reuters Pharma, update of May 29, 2012).
The structures were not communicated.
JNJ-10181457 (Johnson & Johnson; Fig. 22) is
in preclinical development for the potential treat-
ment of narcolepsy and cognitive disorders including
schizophrenia [921]. Another orally active H3 recep-
tor antagonist JNJ-39220675 is developed in Phase II
trials for allergic rhinitis and for treatment of alcohol
dependence [922] (Thomson Reuters Pharma, update
of March 26, 2012). The structure of JNJ-39220675
was not disclosed.
Ligand Pharmaceuticals (following its acquisition
of Neurogen) is investigating a series of orally active
small molecule H3 inverse agonists for the potential
treatment of cognitive disorders (Thomson Reuters
Pharma, update of May 16, 2012). The structures were
not communicated.
SUVN-G1031 (Suven Life Sciences) is a potent
selective H3 receptor antagonist for the treatment of
cognitive deficits. A 4,5-dihydrobenzo[1,4]oxazepine-
3-one (Fig. 22) was presented at the 243rd ACS
Meeting in San Diego March 2012. The compound
increased the release of cognitive-enhancing neuro-
transmitters and was efficacious in in vivo models of
cognition (Thomson Reuters Pharma, update of April
16, 2012).
The development of several cognition enhancing
histamine H3 receptor antagonists (or inverse agonists)
was terminated, of ABT-239 (Abbott [923–926]),
ABT-834 (Abbott), APD-916 (Arena Pharmaceuti-
cals), AQ-0145 (The Green Cross Corp. & Misubishi
Chemical [927]), ATH-90879 (Athersys), cipralisant
(GT-2331; Gliatech [928]), FUB-181 (Freie Univer-
sity Berlin [929, 930]), GSK-189254A, GSK-239512,
GSK-334429, and GSK-357868 (GSK [931–936]),
GT-2016 (Gliatech [937]), histamine H3 antag-
onists (Athersys), MK-0249 (Merck [938–941]),
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors 827

Fig. 23. Two liver X receptor agonists, a nociceptin receptor antagonist and ligands for peripheral benzodiazepine receptors.

PF-03654746 (Pfizer [942–944]), PF-03654764 downregulation of plasma membrane insulin receptors

(Pfizer [943]), thioperamide (INSERM and Bioprojet
[945–950]), TISQ (Lilly), UCB-2892 (UCB), and of
WAY-361046 and WAY-361754 (Wyeth, now Pfizer
[951]).
1.15. Insulin receptors
Soluble A␤ oligomers, also referred to as A␤-
derived diffusible ligands (ADDLs), cause a major
via a mechanism sensitive to calcium calmodulin-
dependent kinase II and casein kinase II inhibition.
This loss of surface insulin receptors could be
completely prevented by insulin. The protection by
submaximal doses of insulin was potentiated by
the PPAR␥ agonist rosiglitazone [952]. The com-
mon pathological processes in AD and diabetes
were reviewed [953–956]. In a population-based neu-
ropathologic study including 553 patients aged >85
828 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
years, it was found that diabetes at baseline doubled
the incidence of dementia [957]. Mice with sys-
temic insulin deficiency displayed evidence of reduced
insulin signaling pathway activity in the brain that is
associated with biochemical and behavioral features
of AD [958]. The common pathway of both diseases
seems to be serine phosphorylation of insulin receptor
substrate 1 (IRS-1). ADDLs activated the JNK/tumor
necrosis factor (TNF)-␣ pathway and induced IRS-1
phosphorylation at multiple serine residues. The neu-
ronal pathology could be prevented by exposure to
the glucagon-like peptide 1 receptor agonist exenatide
(exendin-4, launched by Amylin Pharmaceuticals and
Lilly) [959]. The insulin receptor expression and activ-
ity in the brains of nondiabetic sporadic AD cases was
analyzed recently [960].
Intranasal insulin (nasal drug delivery device
by Kurve Technology) was administered to patients
with amnestic MCI (n = 64) and with mild to mod-
erate AD (n = 40) in a randomized, double-blind,
placebo-controlled clinical trial. Participants received
placebo (n = 30), 20 IU of insulin (n = 36), or 40
IU (n = 38) for 4 months. Treatment with 20 IU of
insulin improved delayed memory and both doses
of insulin preserved caregiver-rated functional ability
[961].
AGT-160 (ArmaGen Technologies) is a recombi-
nant IgG fusion protein formed by the fusion of a single
chain Fv (ScFv) antibody against A␤ plaque forma-
tion to the company’s human insulin receptor-targeting
monoclonal antibody Trojan horse for transport across
the blood-brain-barrier for the potential detection and
treatment of AD (Thomson Reuters Pharma, update of
January 23, 2012).
SYN-20090510RU (SuliXen; SynBio in collabora-
tion with Xenetic Biosciences) is a long-acting insulin
formulation, which incorporates bacterial polysialic
acid for the potential injectable treatment if type 1 and
2 diabetes and neurological disorders such as AD [962]
(Thomson Reuters Pharma, update of June 14, 2012).
1.16. Liver X receptors
The liver X receptors LXR␣ and LXR␤ are mem-
bers of the nuclear hormone receptor family and are
involved in the regulation of cholesterol and lipid
metabolism. Disordered cholesterol balance in the
brain is a hallmark of several neurological disorders
including AD [963, 964]. Treatment with the liver
X receptor agonist T0901317 (Fig. 23) ameliorated
A␤ pathology and memory deficits caused by high-
fat diet in A␤PP23 mice [965]. The ATP-binding
cassette transporter A1 mediated the beneficial effects
of the liver X receptor agonist GW3965 (GSK, Fig. 23)
on object recognition memory and A␤ burden in
A␤PP/PS1 mice [966]. Liver X receptor agonist treat-
ment promoted A␤ degradation and rescued olfactory
behavior in Tg2576 mice [967]. Activation of liver X
receptors promoted neuroprotection and reduced brain
inflammation in experimental stroke [968].
Madera Biosciences is investigating small molecule
therapeutics that increase apolipoprotein E and ATP
binding cassette transporter 1 (ABCA1) levels in the
brain. Pre- and post-traumatic brain injury treatment
of mice with the liver X-receptor agonist T0901317
(Fig. 23 [969]) increased ABCA1 levels at 24 hours
post-injury and reduced the traumatic brain injury-
induced increase of A␤ [970]. Targeted diseases are
AD, age-related macular degeneration, and traumatic
brain injury (Thomson Reuters Pharma, update of
April 20, 2012).
The development of LXR agonists of Anagen Thera-
peutics and the University of Chicago, of AstraZeneca
[963], and of GSK investigating the research tool GW-
3965 for the treatment of inflammatory CNS disorders
was discontinued [971].
1.17. Neurotensin receptors
The expression levels of neurotensin receptor 1
(NTSR1) and of NTSR2 were profoundly decreased
in AD, whereas mRNA levels of neurotensin only
declined slightly and those of NTSR3 (which is
involved in neuronal apoptosis) did not vary [972].
NT-69-L (Mayo Foundation) is a neurotensin
hexapeptide of disclosed structure acting as neu-
rotensin receptor agonist for the potential treatment of
pain, schizophrenia, AD, Parkinson’s disease, nicotine
and alcohol dependence, and CDS [973–978] (Thom-
son Reuters Pharma, update of February 22, 2011).
1.18. Nociceptin (ORL1) receptors
The nociceptin system and hippocampal cognition
in mice was investigated [979]. Activation of the
nociceptin receptor impaired recognition memory in
rodents [980].
PF-454583 (Fig. 23) and PF-4926965 (Pfizer) are
opioid receptor-like 1 (ORL1) receptor antagonists in
preclinical development. PF-454583 had a Ki value
of 8 nM. At doses of 0.1 and 0.32 mg/kg its reversed
scopolamine-induced deficits to an extent comparable
to that of donepezil at 3.2 mg/kg (Thomson Reuters
Pharma, update of August 4, 2011).
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
The development of NNC-63-0532 and NNC-63-
0780 (Novo Nordisk) for treatment of anxiety and
dementia was terminated [981, 982].
1.19. Opioid receptors
The interactive influence on pain, cognition, and
emotion by endogenous opioid peptides was eluci-
dated [983]. Activation of ␮-opioid receptors led to
an enhancement of cognition in rats [984]. A review
on the opioid system and AD was published in 2012
[985].
The development of GR-86014 and GR-91272
(GSK, potent κ opioid receptor agonists [986–989])
and of RDC-5768 (Alkermes, an antagonist on h␮ and
δ opioid receptors and a partial agonist at hκ opioid
receptors) was terminated [353].
1.20. Peripheral benzodiazepine receptors (PBRs)
AD is associated with local glial responses in
the brain parenchyma, which involves activation of
microglia. The mitochondria of these cells express
increased amounts of PBRs [990, 991]. This increase of
PBRs can be measured quantitatively via PET imaging.
In a clinical study, 13 AD patients and 10 controls
had 11 C-(R)-PK11195 (Fig. 23) PET scans. Region
of interest analyses detected a significant 20–35%
increase of microglial activation in frontal, tempo-
ral, parietal, occipital, and cingulate cortices (p < 0.05)
of the AD subjects. 11 C-PIB PET revealed a signifi-
cant two-fold increase in A␤ load in the same cortical
areas (p < 0.0001). Mini-Mental Status Exam (MMSE)
scores in AD subjects correlated with levels of corti-
cal microglial activation but not with A␤ load. The
inverse correlation between MMSE and microglial
activation is compatible with the role of microglia
in neuronal damage [990]. Patients with idiopathic
Parkinson’s disease show significantly increased mean
levels of 11 C-(R)-PK11195 binding in pons, basal
ganglia, and frontal and temporal cortical regions com-
pared with control subjects [992]. Similar results were
found in patients with progressive supranuclear palsy
[993].
11 C-Vinpocetine (Gedeon Richter, Fig. 23) dis-
played a significantly higher brain uptake than
11 C-(R)-PK11195 to reach PBRs in human brain [994,
995].
11 C-DAA-1106 (Taisho Pharmaceuticals, Fig. 23)
has a very high affinity to PBRs in mitochon-
drial fractions of rat (Ki = 0.043 nM) and monkey
(Ki = 0.188 nM) brains. logP is 3.65. This compound
829
has a four times higher uptake in vivo than PK11195 in
monkey brain [996–1001]. A comparative autoradiog-
raphy study in postmortem whole hemisphere human
brain slices was reported [1002]. An improved syn-
thesis was worked out [1003]. The development of
DAA-1106 as a drug for the potential treatment of
anxiety disorders was terminated (Thomson Reuters
Pharma, update of December 5, 2011).
18 F-FEDAA-1106 (ZK-6032924, BAY-85-8101;
Bayer under license from Taisho Pharmaceuticals;
Fig. 23) is an i.v. injectable PET ligand for potential
diagnostic imaging of AD and multiple sclerosis. For
the synthesis, see [1004, 1005]. A Phase I study in AD
(n = 55) was initiated in June 2007 in Sweden and the
Netherlands, a second Phase I study in January 2009
in MS (n = 30) in Sweden and Australia (Thomson
Reuters Pharma, update of March 27, 2012).
SSR-180575 (sanofi, Fig. 23) is a PBR agonist
that stimulated nerve growth and was developed
for the potential treatment of diabetic neuropa-
thy [1006–1008]. Although its development as an
anti-diabetic drug was terminated the radioligand
11 C-SSR-180575 is a valuable tool to measure neu-
roinflammation in the brain [1009, 1010] (Thomson
Reuters Pharma, update of February 14, 2011).
BAY-85-8102 (18 F-DPA-714, F-18-DPA-714;
Bayer in collaboration with INSERM under license
from the University of Sydney, Fig. 23) is no longer
developed as an imaging agent for patients with AD.
It is in Phase I clinical evaluation for the imaging of
patients with amyotrophic lateral sclerosis (Thomson
Reuters Pharma, update of March 27, 2012).
1.21. Peroxisome proliferator-activated receptors
(PPARs)
The nuclear receptor PPAR␥ is a ligand-activated
transcription factor, whose biological actions are to
regulate glucose and lipid metabolism and to suppress
inflammatory gene expression [1011, 1012]. The neu-
roprotective mechanisms of PPAR agonists in AD were
reviewed pointing to the anti-amyloidogenic, anti-
inflammatory, insulin-sensitizing, and cholesterol-
lowering potential of PPAR␥ agonists [1013].
Rosiglitazone (Avandia, GSK; Fig. 24) has been
evaluated in several Phase III clinical trials for the
treatment of AD. The argument was that rosiglitazone
may reduce the physiological resistance to insulin,
which could potentially reduce the level of A␤ in the
blood. Insulin protected against the ADDL-induced
downregulation of plasma membrane insulin receptors.
830 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 24. PPAR␥ agonists, two prostaglandin E2 and a RAGE antagonist(s).
The protection by submaximal doses of insulin was
potentiated by rosiglitazone [1014].
In clinical studies, neither the 2 mg nor the 8 mg
dose offered a statistically significant therapeutic ben-
efit to mild to moderate AD patients [1015]. GSK
discontinued all clinical trials of rosiglitazone in AD.
In 2011 rosiglitazone was withdrawn from the mar-
ket in Europe and is available in the US only under
severe restrictions (Thomson Reuters Pharma, update
of June 13, 2012). Recent preclinical results con-
firm that rosiglitazone enhanced synaptic plasticity in
experimental animals [1016, 1017].
Pioglitazone (Actos, Takeda, launched in 1999;
Fig. 24) has been tested in five randomized controlled
Phase II trials on cognition in AD patients [1018]. So
far no results have been communicated. In November
2011, Takeda and Zinfandel Pharmaceuticals initi-
ated Phase I trials of pioglitazone using Zinfandel’s
TOMM40 biomarker assay to identify subjects at risk
of developing AD in the US and in EU. Pioglita-
zone attenuated mitochondrial dysfunction, cognitive
impairment, and inflammation following traumatic
brain injury [1019]. For a comment, see [1020]. NMDA
receptors are involved in the beneficial effects of piogli-
tazone on scopolamine-induced memory impairment
in mice [1021]. The effect of pioglitazone on insulin
resistance correlated with RAGE inhibition [1022]
(Thomson Reuters Pharma, update of June 21, 2012).
Mitoglitazone (MSDC-0160; Metabolic Solutions
Development Co; Fig. 24), the active metabolite of
pioglitazone, is an insulin-sensitizing, PPAR␥-sparing
thiazolidine-dione with antihypertensive and lipid-
lowering properties. In July 2011, a Phase IIa study
in mild AD patients began and was finished by Febru-
ary 2012. The data showed this novel once-a-day oral
insulin sensitizer, the first in a new class of therapeutic
agents called mTOT modulators, met the study’s pri-
mary endpoint of significantly reducing fasting plasma
glucose in patients diagnosed with type 2 diabetes,
and significantly reduced hemoglobin A1c (Thomson
Reuters Pharma, update of June 20, 2012).
DSP-8658 (Dainippon Sumitomo, one compound
of this series is shown in Fig. 24) is a dual PPAR␣/␥
agonist, which also reduces A␤ levels, for the poten-
tial treatment of diabetes and AD. A Phase I clinical
trial in patients with AD started in February 2011 in
the US (Thomson Reuters Pharma, update of February
21, 2012). The synthesis and pharmacological eval-
uation of DSP-8658 were published recently [1023,
1024].
G-15750 (Genfit) is active against PPAR␥ recep-
tors and acts as a nootropic agent (Thomson Reuters
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Pharma, update of November 30, 2010). The structure
was not communicated.
Roche is investigating a series of dual gamma
secretase/PPAR␥ modulators based on the structure of
2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid
in collaboration with scientists from the University
of Frankfurt am Main for the potential treatment of
AD [1025, 1026] (Thomson Reuters Pharma, update
of April 1, 2011).
1.22. Prostaglandin receptors
Impaired cognition was observed in mice lacking
the prostaglandin E2 (EP2) receptor [1027]. EP2 stim-
ulated the production of A␤ through internalization
of the EP4 receptor [1028]. Improvement of cognitive
function was observed in AD A␤PP23 mice by genetic
and pharmacological inhibition of the EP4 receptor
[1029].
Amgen is investigating EP2 antagonists for the
potential treatment of AD. A lead compound (Fig. 24)
was identified with moderate i.v., pharmaco-kinetic
properties in mice, a Cmax of 1.2 ␮M and an oral
bioavailability of 31%. The compound demonstrated
good CNS permeability. It significantly increased A␤
phagocytosis and had an IC50 value of 8 nM for EP2
receptors (Thomson Reuters Pharma, update of March
29, 2012).
TG-6-10-1 (Emory University; Fig. 24) is the lead
compound of EP2 receptor antagonists for the potential
treatment of inflammation associated with neurologi-
cal disease such as AD, Parkinson’s disease, stroke,
traumatic brain injury, migraine, and neuropathic pain
[1030] (Thomson Reuters Pharma, update of June 8,
2012).
1.23. Purinergic receptors
P2X7 receptors were specifically upregulated
around A␤ plaques in the Tg2576 mouse model of
AD [1031, 1032]. Blockade of P2X7 receptors with the
P2X7R antagonist brilliant blue G was neuroprotective
in an animal model of AD [1033, 1034]. Activation
of the purinergic receptor P2X7 stimulated sA␤PP␣
release from mouse neuroblastoma cells expressing
human A␤PP [1035]. P2X7 receptors expressed in hip-
pocampal and glial cells may be a potential therapeutic
target in AD.
Axxam SpA is investigating a series of P2X7
purinoceptor antagonists for the potential treatment
of autoimmune diseases including AD and pain. The
company received a grant from the Alzheimer’s Drug
831
Discovery Foundation (Thomson Reuters Pharma,
update of June 23, 2011).
1.24. Receptor for advanced glycation end
products (RAGE)
RAGE mediates amyloid-peptide transport across
the blood-brain barrier back into the brain leading to a
potential accumulation of A␤ in the brain as was shown
in in vitro experiments [1036] and in in vivo exper-
iments [1037]. See also [1038]. The role of RAGE
as therapeutic target to promote neuroprotection was
discussed [1039].
TTP-4000 (Pfizer under license from Trans Tech
Pharma) is a fusion protein containing the extracellular
portion of the RAGE. In March 2012, a random-
ized, double-blind, placebo-controlled, Phase I study
(NCT01548430) was initiated in patients with AD
(expected n = 16) in the US to assess the safety and
pharmacokinetics (Thomson Reuters Pharma, update
of April 9, 2012). The structure of TTP-4000 was not
communicated.
Other RAGE antagonists are currently in preclinical
evaluation (in alphabetical order):
DBT-066 (Roche under license from Digital Biotech
and the Seoul National University) is a RAGE antago-
nist that blocks the entry of A␤ to the brain (Thomson
Reuters Pharma, update of April 28, 2010). The struc-
ture was not communicated.
FPS2-BM and FPS-ZM1 (Socratech, a spin-off
of the University of Rochester; Thomson Reuters
Pharma, update of March 15, 2012). The structure
of FPS-ZM1 (Fig. 24) deriving from a secondary
screen was communicated [1040]. It is a high affinity
RAGE-specific inhibitor that blocked A␤ binding to
the V domain of RAGE and inhibited A␤40 and A␤42 -
induced cellular stress in RAGE-expressing cells in
vitro and in the mouse brain in vivo. FPS-ZM1 inhib-
ited RAGE-mediated influx of circulating A␤40 and
A␤42 into the brain. In brain FPS-ZM1 bound exclu-
sively to RAGE, which inhibited ␤-secretase activity
and A␤ production and suppressed microglia activa-
tion and the neuroinflammatory response. Blockade of
RAGE actions at the blood-brain barrier and in the
brain reduced A␤40 and A␤42 levels in brain markedly
and normalized cognitive performance and cerebral
blood flow responses in aged A␤PPsw/0 mice.
Hermo Pharma Oy is investigating a series of small
molecule RAGE antagonists for the potential treatment
of neurodegenerative diseases including AD (Thom-
son Reuters Pharma, update of December 13, 2011).
Structures were not disclosed.
832 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
MabPrex is investigating a series of RAGE antago-
nists for the potential treatment of AD and diabetic
nephropathy (Thomson Reuters Pharma, update of
August 5, 2011). Structures were not disclosed.
A-992401 (Abbott Laboratories) is a monoclonal
antibody targeting RAGE (Thomson Reuters Pharma,
update of December 1, 2010).
Pfizer scientists have published the pharmacokinet-
ics and lung distribution of a humanized anti-RAGE
antibody in wild type and RAGE –/– mice [1041].
An aqueous orally active vaccine targeted against a
RAGE/AB complex was described in 2012 [1042].
The development of the RAGE antagonist PF-
04494700 (TTP-488; Pfizer under license from Trans
Tech Pharma) was terminated. Analysis of the low-
dose group (10 mg/d after a 6-d loading dose of
30 mg/d) showed a favorable outcome for Alzheimer’s
Disease Assessment Scale-cognitive subscale (ADAS-
cog) at month 18 [1043]. Although there were no safety
concerns with this group, the high-dose group (20 mg/d
after a loading dose of 60 mg/d) was discontinued at
6 months due to safety concerns as well as increased
ADAS-cog decline which appeared to slow after the
drug was stopped. The results did not support contin-
ued development of PF-04494700 for AD (Thomson
Reuters Pharma, update of December 8, 2011).
1.25. Retinoid X receptors
Goodman discussed the topic retinoid receptors,
transporters and metabolizers as therapeutic targets in
late onset AD already in 2006 [1044]. Retinoids may
be valuable therapeutic agents in disorders of social
cognition including autism [1045].
Bexarotene (Targretin, LGD-1069; Eisai; Fig. 25)
is a retinoid X receptor agonist launched by Eisai
in 2006 in the US and in Western Europe for the
treatment of cutaneous T-cell lymphoma. Scientists
from the Case Western Reserve University found that
after oral administration to a murine model of AD
bexarotene caused enhanced clearance of soluble A␤
within hours in an apolipoprotein E (ApoE)-dependent
manner. ApoE expression is transcriptionally induced
through the action of the nuclear receptors PPAR␥
and liver X receptors in coordination with retinoid X
receptors. A␤ plaque area was reduced by 50% within
72 hours. Bexarotene stimulated the rapid reversal of
cognitive, social, and olfactory deficits and improved
neutral circuit function [1046]. However, it is likely
that this approach will be limited for patients having
the ApoE4 isoform (Thomson Reuters Pharma, update
of February 14, 2012).
Tamibarotene (Am80; Nippon Shinyaku under
license from the University of Tokyo; Fig. 25) is a
retinoid receptor agonist launched for the treatment
of acute promyelocytic leukemia. In a collaboration
of the Osaka City University, Itsuu Laboratory, and
Kumamoto University, tamibarotene is evaluated as an
orally active nootropic agent in a randomized, placebo-
controlled, Phase II clinical trial in patients with AD
(n = 50) in Japan since May 2010. The dosage is 4 mg
four times a day (qid) [1047, 1048] (Thomson Reuters
Pharma, update of September 8, 2011).
1.26. Ryanodine receptors
Ryanodine receptors located within the membrane
of the endoplasmic reticulum mediate the release of
calcium ions into the cytoplasm. Mutations in the genes
of presenilin-1 and presenilin-2 significantly increase
the expression and activation of ryanodine receptors
[1049–1051].
Dantrolene (JHP Pharmaceuticals) is a well-known
muscle relaxant and ryanodine receptor inhibitor. It
ameliorated cognitive decline and neuropathology in
triple transgenic AD mice [1052].
1.27. Serotonin receptors
The topic serotonin and human cognitive perfor-
mance was reviewed [390, 1053]. Serotonin receptors
represent highly favorable molecular targets for cogni-
tive enhancement in schizophrenia and other disorders
[1054]. Abundant data revealed that administration of
5-HT2A/2C and 5-HT4 receptor agonists, or of 5-HT1A ,
5-HT3, and 5-HT1B antagonists improved memory and
had a facilitatory effect on learning in situations involv-
ing a high cognitive demand. Also the role of 5-HT7
receptors in the modulation of cognitive processes was
studied in depth [1055–1057].
1.27.1. 5-HT1A receptor agonists and antagonists
The role of 5-HT1A receptors in the pathophysi-
ology of schizophrenia was reviewed [1058, 1059].
The role of 5-HT1A receptors in learning and memory
was discussed [1060, 1061], as was the modulation of
cholinergic functions by serotonin and possible impli-
cations in memory with focus on 5-HT1A receptors
[1062]. 5-HT1A agonism was adequate to ameliorate
the PCP-induced impairment of novel object recogni-
tion deficits in rats [1063]. A PET study of 5-HT1A
receptors using [11 C]-WAY-100635 was carried out in
10 patients with mild to moderate AD [1064].
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Fig. 25. Two retinoid X receptor agonists, a 5-HT1A receptor, three 5-HT4 receptor agonists and a 5-HT4 receptor antagonist PET ligand.
F-15599 (Pierre Fabre, Fig. 25) is a preferential
postsynaptic 5-HT1A receptor agonist showing a favor-
able profile in models of cognition in comparison to
reference 5-HT1A receptor agonists such as F-13714.
F-15599 is currently in preclinical evaluation for the
potential treatment of depression [1065–1069] (Thom-
son Reuters Pharma, update of March 14, 2011).
[18 F]F15599 was used as a novel radioligand for PET
neuroimaging [1070].
The development of many 5-HT1A receptor ago-
nists and antagonists was terminated (in alphabetical
order), of adatanserin (Wyeth, a combined 5-
HT1A agonist and 5-HT2 antagonist), AP-159 (Asahi
Kasei Pharma; a 5-HT1A receptor agonist [1071]),
F-15063 (Pierre Fabre; a high efficacy 5-HT1A recep-
tor agonist [1072–1074]), of the 5-HT1A receptor
antagonist lecozotan (SRA-333) (Wyeth, now Pfizer
[1075, 1076]) and of its backup compound SRA-
444, robalzotan (NAD-299; AstraZeneca; a 5-HT1A
receptor antagonist [1077]), WAY-100635 (Wyeth,
Pfizer [1077–1081]), WAY-101405 ([1082]) and of
xaliproden (sanofi), which stimulated endogenous
neurotrophin synthesis and prevented p75-mediated
apoptosis [1083]. Xaliproden was evaluated in sev-
eral Phase III clinical trials in AD and in amyotrophic
833
lateral sclerosis patients, which turned out to be disap-
pointing [1084, 1085].
1.27.2. 5-HT2 receptor antagonists
The role of 5-HT2A receptors in learning was
reviewed [1086]. The 5HT2A antagonist mianserin
improved performance in selective neurocognitive
tests as an add-on medication to typical antipsychotics
in chronic schizophrenia patients [1087].
Asenapine (Organon, Schering-Plough, now Merck
& H. Lundbeck) is a 5-HT2A and dopamine D1 /D2
antagonist launched as a sub-lingual formulation for
the treatment of schizophrenia in adults. Asenapine
restored cognitive flexibility in rats with medial pre-
frontal cortex lesions suggesting that asenapine may
be beneficial for cognitive deficits in schizophrenic
patients [1088]. Asenapine improved phencyclidine-
induced object recognition deficits in rats [1089].
The development of AP-267 (AcurePharma AB,
a 5-HT2 C receptor-modulating compound [1090]),
of dual 5-HT2 C and 5-HT6 receptor antagonists
(Korea Research Institute of Chemical Technology)
and of EGIS-11150 (EGIS, now Servier), binding
to 5-HT2A and 5-HT7 receptors with Ki values of
3.1 nM and 22 nM and to ␣1-adrenoceptors with a Ki
834 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
of 0.55 nM was terminated (Thomson Reuters Pharma,
update of March 7, 2011).
1.27.3. 5-HT3 receptor antagonists
Cognitive implications for histamine H3 and 5-HT3
receptor modulation of cortical cholinergic function
were elucidated [1091] as was the role of 5-HT3 recep-
tors in selective animal models of cognition [1092].
The development of itasetron (DAU-6215; Istituto
di Angeli, Boehringer Ingelheim; a 5-HT3 recep-
tor antagonist [1093]) and of MCI-225 (Mitsubishi
Pharma and Taisho [1094–1096]) was terminated.
1.27.4. 5-HT4 receptor (partial) agonists
The 5-HT4 receptor is a G-protein-coupled, 7-
transmembrane domain protein positively linked to the
activation of adenylcyclase [1097]. The highest densi-
ties of 5-HT4 receptors within the CNS are located in
limbic regions including hippocampus, frontal cortex,
and amygdala. The 5-HT4 receptor agonist RS-17017
enhanced delayed matching performance in young and
older macaques [1098]. These effects may be due to an
increase of the release of acetylcholine and an enhance-
ment of the amplitude of tetanus-induced long-term
potentiation [1099, 1100]. The 5-HT4 receptor par-
tial agonist capeserod (SL65.0155, sanofi) reversed
cognitive deficits in animal behavioral tasks without
peripheral side effects. Capeserod acted synergistically
with the cholinesterase inhibitor rivastigmine [1101].
The role of 5HT4 receptors in learning and memory
has been reviewed [1102].
French scientists at the University of Paris-Sud
found that 5-HT4 receptor agonists shift the process-
ing of A␤PP to the non-amyloidogenic ␣-secretase
pathway leading to a strong stimulation of the release
of neurotrophic and neuroprotective soluble A␤PP␣
and concomitantly to a decrease of extracellular A␤
peptides [1103–1107]. These data were confirmed
independently by a group at Wyeth Pharmaceuticals
[1108] and at the University of Copenhagen [1109].
The effect is isoform specific, because activation of
h5-HT4(d) is more efficient in enhancing levels of
sA␤PP␣ than the activation of h5-HT4(e/g) . The highly
selective 4-HT4 receptor agonists prucalopride and
ML-10302 injected s.c. to male C57BL/6 j mice sig-
nificantly increased sA␤PP␣ levels in hippocampus
and cortex [1110]. Furthermore the combined injec-
tion of the selective acetylcholinesterase inhibitor
donepezil and of prucalopride induced a synergistic
increase in sA␤PP␣ levels in the cortex and hip-
pocampus and reversed scopolamine-induced memory
deficits [1111]. For excellent medicinal chemistry
from the group at the University of Paris-Sud, see
[1112].
PRX-3140 (Nanotherapeutics, Fig. 25) is a 5-HT4
receptor agonist in Phase II clinical trials for treat-
ment of AD and post-traumatic stress disorders since
December 2009 (Thomson Reuters Pharma, update of
June 11, 2012). Data on the enhancement of cognitive
function in vivo were communicated [1113].
Velusetrag (TD-5108, Theravance; Fig. 25) was
listed as being in Phase I trials for AD in July 2010
(Thomson Reuters Pharma, update of January 12,
2012). Its in vitro pharmacological profile was pub-
lished [1114]. Another potential use is treatment of
gastrointestinal motility disorders [1115].
RQ-00000009 (RaQualia, Pfizer) is a selective 5-
HT4 receptor partial agonist for the treatment of AD.
A Phase I study was initiated in August 2008 (Thom-
son Reuters Pharma, update of May 15, 2012). The
structure was not disclosed.
SUVN-D1003019 and SUVN-1004028 (Suven Life
Sciences) are selective 5-HT4 receptor agonists for
the treatment of MCI, cognition, and AD. A 4-
hydroxyquinolinone with good oral exposure, brain
penetration, moderate clearance, good half-life in rats,
and efficacy in in vivo cognition tests was presented
at the 243rd ACS Meeting in San Diego March 2012
(Fig. 25; Thomson Reuters Pharma, update of April
16, 2012).
GSK terminated the development of the 5-HT4
antagonist PET ligand 11 C-SB-207145 (Fig. 25;
Thomson Reuters Pharma, update of April 3, 2012).
The ligand is still extensively used for brain imag-
ing of 5-HT4 receptors in academic settings [1109,
1116–1120]. Also the tritiated ligand 3 H-SB-207145
is extensively used for 5-HT4 receptor binding studies
[1121, 1122].
The development of BIMU-1 and BIMU-8
(Boehringer Ingelheim [1123–1125]), capeserod (SL-
65.0155; sanofi [1101, 1126–1129]), of the 5
HT4 antagonist GR-113808 (GSK [1130, 1131]),
ML-10302 (sanofi [1132]), PF-04995274 (Pfizer),
RS-56532 and RS-66331 (Roche [1133, 1134]),
SC-53116 (Searle, Pfizer [1135, 1136]), TD-8954
(Theravance [1113, 1137]; however, the development
for the treatment of gastrointestinal motility disor-
ders is continuing) and of VRX-03011 (Epix Pharma
[1138]) was terminated.
1.27.5. 5-HT6 receptor antagonists
5-HT6 receptors are almost exclusively localized in
the CNS [1139]. They are positively coupled to adeny-
lyl cyclase. Extensive preclinical research supports a
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors 835

Fig. 26. 5-HT6 receptor antagonists.

model of neural circuitry in which the tonic activation
of 5-HT6 receptors expressed on GABAergic neurons
leads to an induction of GABA release and in turn
to an inhibition of cholinergic and glutamatergic neu-
rons. Blockade of 5-HT6 receptors effectively removes
this tonic GABAergic inhibition of downstream neu-
rons resulting in enhanced neurotransmission of at
least acetylcholine and glutamate [1140–1148]. An
excellent overview of the effects of 5-HT6 receptor
antagonists in ten cognitive paradigms (Morris water
maze, passive avoidance, conditioned operant respond-
ing, reward-motivated learning behavior, novel object
recognition, social recognition, attentional set shifting,
pre-pulse inhibition of acoustic startle, latent inhibition
and five-choice serial reaction time and delayed reward
tasks) was presented [1149]. A functional human 5-
HT6 receptor assay for high throughput screening
[1150] and a chemocentric informatics approach were
described [1151].
Latrepirdine (Dimebon; Dimebolin; Medivation,
Pfizer; Fig. 26) is an orally bioavailable antihistamine
drug discovered in Russia used for the treatment of
skin allergy and allergic rhinitis since 1983. In 2000,
additional preclinical experiments revealed that dime-
bon improved learning in animal models of AD [1152,
1153] acting as a cognition enhancer [1154]. The
836 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
drug was taken into a Phase II clinical trial in AD
(n = 183, 10 mg three times a day for 7 days, increased
to 20 mg three times a day for the remainder of the
study or placebo for 26 weeks) and showed a significant
improvement in cognitive function on the ADAS-cog
in the dimebon group and worsening in the placebo
group (mean change from baseline −1.9 with dimebon,
versus +2.1 with placebo, difference −4.0, p < 0.0001
[1155]). Pfizer started several Phase III clinical trials in
AD and in Huntington’s disease [1156], but the promis-
ing data of the Phase II trial could not be repeated
[1157].
Pfizer and Medivation discontinued the develop-
ment of latrepirdine for the treatment of AD and
Huntington’s disease, which was communicated on
January 17, 2012.
There is a longstanding debate on the mecha-
nism of action of latrepirdine in AD [1158]. It
is a potent 5-HT6 receptor antagonist with acute
cognition enhancing properties (Ki = 26 nM for h5-
HT6 receptors; Ki = 119 nM for r5-HT6 receptors)
[1159, 1160]. The receptor profile is H1 recep-
tor: IC50 = 3.8 nM, H2 receptor: IC50 = 287 nM; ␣1A
and ␣1B receptors: Ki = 74–86 nM, ␣1D , ␣2A and
I2 receptors: Ki = 261–313 nM, but no binding to
␤ adrenoceptors; 5-HT7 receptor: Ki = 8 nM, 5HT6
receptor: Ki = 34 nM, 5-HT2C receptor: Ki = 76 nM,
5-HT2A receptor: Ki = 61 nM; D1 = D2S = D2L recep-
tors: Ki = 600 nM; inhibition of butyryl cholinesterase:
IC50 = 7.9 ␮M, inhibition of acetylcholinesterase:
IC50 = 42 ␮M [1161]. The cognition-enhancing prop-
erties of dimebon in a rat novel object recognition
task are unlikely to be associated with acetyl-
cholinesterase inhibition or NMDA receptor antago-
nism (Ki = 105 ␮M) [1162]. Other scientists claim that
its main action is the improvement of mitochondrial
function in the setting of cellular stress [1163, 1164].
After acute dosing of latrepirdine, extracellular levels
of A␤ levels were elevated in vitro and in vivo [1165].
In the brains of TgCRND8 mice chronically treated
with dimebon, levels of total A␤ as well as of solu-
ble oligomeric A␤ were unchanged [1166]. Studies in
young adult and aged Rhesus monkeys showed that
dimebon produced statistically significant increases in
delayed matching-to-sample task accuracies [1167].
Dimebon slowed the progression of proteinopathy in
␥-synuclein transgenic mice [1168].
The potential PET agent [11 C]-Dimebon was
prepared [1169].
Biovista is evaluating latrepirdine for the potential
oral treatment of multiple sclerosis in a novel formu-
lation BVA-101 (Thomson Reuters Pharma, update of
December 6, 2011) and for the potential oral treatment
of epilepsy in another formulation BVA-601 (Thomson
Reuters Pharma, update of October 3, 2011).
Lu-AE58054 (LY-483518; SGS-518; Lundbeck
under license from Lilly; Fig. 26) is currently in
Phase II clinical development since November 2009.
In May 2012 Lundbeck reported that the fixed dose,
randomized trial conducted in Europe, Canada, and
Australia met its primary endpoint. Data demonstrated
that Lu-AE58054 plus donepezil (10 mg/day) signifi-
cantly improved cognitive function in 278 patients with
AD compared to placebo plus donepezil, when mea-
sured by ADAS-cog. Lu-AE58054 showed positive
results in the secondary endpoints including measures
of global status and daily living activities compared to
donepezil treated patients (Thomson Reuters Pharma,
update of May 29, 2012). The reversal of cognitive
impairment induced by subchronic phencyclidine in
rats was described [1170]. The characterization of
the tritiated ligand [3 H]Lu AE60157 (Fig. 26) bind-
ing to 5-HT6 receptors in vivo was communicated
[1171].
SB-742457 (GSK, Fig. 26) entered Phase II clini-
cal trials for the oral treatment of AD in September
2005 (n = 371, 24 weeks treatment of 5 mg, 15 mg, or
35 mg once daily in comparison to placebo). Another
Phase II trial was initiated in July 2008 (n = 672;
NCT00710684). The results of the clinical studies were
reported showing a statistically significant improve-
ment of the patients on the CIBC+ scale, but not at
the ADAS-cog [1172, 1173]. The interaction between
risperidone and SB-742457 in healthy men was inves-
tigated [1174]. The amelioration of memory deficits
induced by scopolamine in Wistar rats was reported
[1175, 1176] (Thomson Reuters Pharma, update of
October 17, 2011).
AVN-101 (Avineuro Pharmaceuticals and Chem-
Div) is a 5-HT6 receptor antagonist for the potential
treatment of AD and anxiety. Phase II clinical trials
were initiated in February 2010 for AD and anx-
iety (Thomson Reuters Pharma, update of August
19, 2011). The structure of AVN-101 was not
disclosed.
AVN-211 (Avineuro Pharmaceuticals and Chem-
Div) is another 5-HT6 receptor antagonist in a Phase II
clinical trial for the potential treatment of CDS since
June 2009. In February 2011 results from the double-
blind, Phase IIa trial in 50 patients showed the trial met
its primary efficacy endpoints and AVN-211 was safe
and well tolerated (Thomson Reuters Pharma, update
of July 14, 2011). The structure of AVN-211 was not
disclosed.
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
AVN-322 (Avineuro Pharmaceuticals and Chem-
Div) was in Phase I clinical trials for the treatment
of AD since June 2009. In March 2010 results showed
the drug was safe and well tolerated with no adverse
events reported (Thomson Reuters Pharma, update of
August 19, 2011). The structure of AVN-322 was not
disclosed.
ABT-354 (SLV-354; Abbott following its acquisi-
tion of Solvay’s pharmaceutical business) is a 5-HT6
receptor modulator in Phase I clinical trials since
February 2010. In March 2012 a Phase I trial began
in schizophrenia patients (n = 22) in the US (Thom-
son Reuters Pharma, update of March 8, 2012). The
structure was not communicated.
SAM-760 (PF-05212377, WYE-103760; Wyeth,
now Pfizer) is in Phase I clinical trials for the treat-
ment of AD since October 2009. Data were presented
[1177]. SAM-760 was found to be safe and well toler-
ated in young and elderly subjects (Thomson Reuters
Pharma, update of May 11, 2012). The structure of
SAM-760 was not disclosed. Medicinal chemistry was
communicated [1178].
SUVN-502 (Suven Life Sciences) is in Phase I clin-
ical trials for the treatment of cognitive disorders in
AD, ADHD, Parkinson’s disease, and schizophrenia
since June 2008 (Thomson Reuters Pharma, update
of May 23, 2012). The structure of SUVN-502 was
not disclosed. Recently novel chemical classes of 5-
HT6 receptor antagonists, i.e., aryl aminosulfonamide
derivatives with a Kb of 0.02 nM were reported and
N1 -arylsulfonyl-3-piperazinyl indole derivatives with
a Ki of 3.4 nM [1179–1183].
SUVN-507 (Suven Life Sciences; Fig. 26) is a 5-
HT6 receptor antagonist (Ki = 1.3 to 1.6 nM) for the
treatment of schizophrenia, MCI, and AD in preclinical
development. Other compounds in preclinical eval-
uation are SUVN-501, SUVN-901, and SUVN-976.
The lead structure has a 7-aza-indole core (Fig. 26).
SUVN-504 is evaluated as drug for the potential treat-
ment of obesity and metabolic disorders including
diabetes (Thomson Reuters Pharma, update of Febru-
ary 8, 2012).
SYN-114 and SYN-120 (Biotie Therapies, formerly
Synosia Therapeutics under license from Roche) are
currently both in Phase I clinical trials for the treatment
of cognitive disorders (Thomson Reuters Pharma,
updates of March 9 and May 7, 2012, respectively).
The structures of SYN-114 and SYN-120 were not
disclosed.
Pyrazolo[1,5-a]pyrimidines (ChemDiv; Fig. 26)
are highly potent 5-HT6 receptor antagonists being
extensively investigated by ChemDiv in San Diego.
837
The compound shown in Fig. 26 displayed a Ki of
0.088 nM [1184–1192] (Thomson Reuters Pharma,
update of May 8, 2012).
5-HT6 receptor antagonists (Abbott Laboratories;
Fig. 26) are evaluated for the potential treatment of
cognitive deficits in patients with AD and schizophre-
nia (Thomson Reuters Pharma, update of December 9,
2011). The medicinal chemistry was described [1193].
The effects to ameliorate scopolamine-induced mem-
ory deficits in object recognition and object location
tasks in Wistar rats were reported [1194].
5-HT6 receptor antagonists (Galenea) are evalu-
ated for the potential treatment of cognitive impairment
associated with schizophrenia (Thomson Reuters
Pharma, update of April 17, 2012). No structures were
communicated.
5-HT6 receptor antagonists (Promaxigen under
license from Swedish Orphan Biovitrum, formerly
Biovitrum) are evaluated for the potential treatment of
cognitive disorders (Thomson Reuters Pharma, update
of May 16, 2012). No structures were communicated.
Intense medicinal chemistry efforts have been car-
ried out over years in companies such as Bristol-Myers
Squibb, Cephalon, Esteve, Galenea, Gedeon Richter,
GSK, Merck, Merz, Redix, Roche, Synosia Therapeu-
tics, and Wyeth (Pfizer), which have been described in
several excellent reviews [1139, 1143, 1195–1203].
The development of the clinical trial compounds A-
964324 (Abbott Laboratories [1193, 1204]), AVN-397
(Avineuro Pharmaceuticals), cerlapirdine (SAM-531,
PF-5212365; Wyeth, now Pfizer [1205, 1206]), E-6801
(Esteve [1207]), 11 C-GSK-215083 (GSK [1208]),
MEM-68626 (Memory Pharmaceuticals, now Roche),
PRX-07034 (Predix Pharmaceuticals [1209]), R-1485
(Roche), Ro-4368554 (Roche [1210–1212]), SAM-
315 (WAY-255315; Wyeth, now Pfizer [1213–1216]),
SB-258510, SB-258585 (GSK [1210]), SB-271046
(GSK [1217–1223]), SB-357134 and SB-399885
(GSK [1223, 1224]) and WAY-101 (Wyeth, now
Pfizer) was terminated.
1.28. Sigma receptors
Excellent reviews on sigma-1 receptors and cogni-
tion were published [1225–1227] complementing the
exhaustive early reference work [1228].
Fluvoxamine (Solvay, now Abbott; Fig. 27) is a
5-HT re-uptake inhibitor and sigma-1 receptor ago-
nist launched in 1994 for the treatment of depression
and obsessive compulsive disorders. Recently it was
reported that fluvoxamine improved cognitive impair-
ment in patients with schizophrenia [1229, 1230].
838 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

Fig. 27. Sigma-1 receptor agonists and antagonists.

Cutamesine (SA-4503; M’s Science under license
from Santen, Fig. 27) is a potent sigma-1 receptor
agonist (Ki = 4 nM) in Phase II clinical trials for the
treatment of CDS and AD, for post-stroke recovery
and depression. The cognition enhancing properties
of SA-4503 were elucidated [1231–1235]. SA-4503
attenuated cocaine- and methamphetamine-induced
hyperactivity [1236, 1237] (Thomson Reuters Pharma,
update of June 20, 2012).
A Sigma-1 receptor antagonist (E-52862; Esteve;
Fig. 27) with Ki values of 0.55 nM and 109 nM for
sigma-1 and sigma-2 receptors, respectively is in Phase
II clinical trials since March 2012 for the indication
pain. The indication cognitive and psychotic disorders
is no longer followed up [1238] (Thomson Reuters
Pharma, update of April 18, 2012).
Anavex-2-73 (AVex-2-73; AN-2; Anavex Life Sci-
ences, Fig. 27), a sigma-1 receptor agonist, is in a
 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Phase I AD trial since March of 2011 [1239] (Thomson
Reuters Pharma, update of June 27, 2012).
Anavex-1-41 (Fig. 27) is a potential back-up
compound [1240–1242] (Thomson Reuters Pharma,
update of June 19, 2012).
MC-113 (M’s Science) is a sigma receptor ago-
nist for the potential treatment of major depression
and CNS diseases including AD (Thomson Reuters
Pharma, update of June 20, 2012). The structure was
not communicated.
(±)-PPCC (University of Trieste; Fig. 27), a novel
sigma-1 receptor ligand, displayed anti-amnesic prop-
erties on cognitive dysfunction induced by selective
cholinergic lesions in rats [1243].
(–)-MR22 (University of Catania; Fig. 27) is a selec-
tive sigma-1 receptor agonist showing anti-amnesic
and neuroprotective actions in rats with selective
cholinergic lesions and amyloid infusion [1244–
1246].
The development of dehydroepiandrosterone
(DHEA; Fidelin, see Fig. 15), an androgen recep-
tor agonist with sigma-1 receptor agonistic properties,
which may be responsible for its cognition enhanc-
ing properties, was terminated [543, 1247] as was the
development of igmesine (JO-1784; Jouveinal, now
Pfizer) [1248–1256], NEBO-178 (Stegram Pharma-
ceuticals, a sigma receptor antagonist that increased
estrogen binding to ER-␤ and dehydroepiandrosterone
levels in the brain), PRE-084 (INSERM Montpellier)
[1256–1262] and of a sigma-1 receptor ligand (UCB,
Fig. 27).
1.29. Somatostatin receptor agonists
The topic somatostatin and AD was reviewed
[1263]. The link between somatostatin receptors,
memory, and AD was discussed [1264]. Somatostatin
receptor subtype 2 and 4 agonists upregulate the activ-
ity of neprilysin, which amongst other neuropeptides
degrades A␤40 and A␤42 and the oligomeric forms of
A␤ [1265–1268]. Hippocampal SSTR4 somatostatin
receptors control the selection of memory strategies
[1269, 1270].
NNC-26-9100 (Novo Nordisk) was a selective
somatostatin subtype-4 receptor agonist (Ki = 6 nM),
which on chronic administration enhanced learning
and memory in SAMP8 mice and reduced A␤(x-42)
brain levels [1271]. It was evaluated for the poten-
tial treatment of glaucoma and cancer, but is not
followed up.
The development of the somatostatin/serotonin
stimulators FK-960 and FK-962 (Fujisawa, now
839
Astellas) was also discontinued. The preclinical char-
acterization of FK-960 was described [1272–1281]
and of FK-962 [1282, 1283]. Also the development of
the somatostatin analogue FR-121196 (Fujisawa, now
Astellas) and of L-363377 (a somatostatin receptor
subtype 2 agonist of Merck) was terminated.
1.30. Sphingosine-1-phosphate receptor
modulators
Mice lacking the sphingosine-1-phosphate receptor
2 displayed working memory deficits [1284].
ABT-363 (Abbott Laboratories) is a sphingosine-
1-phosphate receptor 5 (S1P5) modulator for the
potential treatment of neurological disorders includ-
ing AD (Thomson Reuters Pharma, update of March
1, 2012). Another S1P1/S1P5 receptor modulator
ABT-413 is evaluated in Phase I clinical trials for
the treatment of multiple sclerosis and rheumatoid
arthritis since July 2011 (Thomson Reuters Pharma,
update of November 28, 2011). Neither structure was
communicated.
1.31. Tachykinin receptor antagonists
The tachykinin (previously known as neurokinin)
receptors are involved in more CNS actions than previ-
ously thought including sleep disorders, amyotrophic
lateral sclerosis, AD, and Machado-Joseph’s disease
[1285]. Neurokinin-3 receptor knockout mice showed
cognitive deficits [1286, 1287].
SSR-241586 (sanofi) is a dual tachykinin
2/tachykinin 3 (previously known as neurokinin)
receptor antagonist for the potential treatment of
irritable bowel syndrome and for positive symptoms
and CDS, depression, and anxiety. Its development
was terminated [1288, 1289].
1.32. Tumor necrosis factor receptor 1 negative
allosteric modulators
125 I-A␤
1-40 binds specifically to TNFR1 in SH-
SY5Y cells with a Kd of 0.42 nM [1290]. A␤ inhibition
of long-term potentiation is mediated by TNF [1291,
1292]. The role of the TNF-␣ signaling pathway lead-
ing to cognitive decline was described [1293, 1294].
TNF-␣ contributed to cognitive deficits after traumatic
brain injury in mice [1295]. A small molecule inhibitor
for TNF-␣ (3,6 -dithiothalidomide) prevented cogni-
tive deficits in a triple transgenic mouse model of AD
[1296, 1297]
840 W. Froestl et al. / Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
130 patients with MCI were followed up for 4–6
years. Those patients, who subsequently developed AD
or vascular dementia, had higher levels of sTNFR1
and sTNFR2 in both CSF and plasma already at base-
line [1298, 1299]. Elevated plasma levels of soluble
CD40, a member of the tumor necrosis factor recep-
tor super-family, have also been found in patients
who converted from MCI to AD [1300]. Improve-
ment of cognition was observed in elderly patients
with rheumatoid arthritis treated with anti-TNF ther-
apy [1301].
Addex Therapeutics is investigating NAMs of
TNFR1 for the potential treatment of rheumatoid
arthritis, psoriasis, AD, and multiple sclerosis (Thom-
son Reuters Pharma, update of June 19, 2012). The
structures were not communicated.
PD-2015 and PD-2016 (P2D Bioscience) are
small molecule TNF-␣ inhibitors. PD-2015 improved
cognitive deficiency in AD transgenic mice and inhib-
ited neuroinflammation (Thomson Reuters Pharma,
update of April 30, 2012). The structures were not
communicated.
CONCLUSION
With the launch of the NMDA receptor channel
blocker memantine for the treatment of moderate to
severe AD in 2002, a valuable medication was added
to the four acetylcholinesterase inhibitors launched
previously (see Part 2). The medical team of Merz
under Hans Jörg Möbius and the many collaborating
clinicians deserve full credit and admiration for an
important breakthrough for the benefit of AD patients.
In January 2012, the development of the Phase
III compound interacting with receptors latrepirdine
for the potential treatment of AD was terminated.
Before latrepirdine, 13 other Phase III compounds
were discontinued, i.e., alvameline, cevimeline, mil-
ameline, sabcomeline, and xanomeline (M1 mAChR
agonists); fasoracetam, nebracetam, and nefirac-
etam (piracetam analogues); dehydro-epiandrosterone
(androgen receptor agonist); neramexane (NMDA
receptor channel blocker); rosiglitazone (PPAR␥ ago-
nist); xaliproden (5-HT1A receptor agonist); and
lecozotan (5-HT1A receptor antagonist). At present
there is no Phase III compound in development as a
cognitive enhancer.
There are currently 27 compounds interacting
with receptors in Phase II clinical trials for the
potential treatment of AD: pozanicline, ispronicline,
AZD-1446, and sofinicline (␣4␤2 nAChR agonists);
ABT-126, EVP-6124, GTS-21, and TC-5619 (␣7
nAChR agonists); tozadenant (adenosine receptor
A2A antagonist); ORM-12741 (␣2C adrenoceptor
antagonist); HT-2157 (galanin-3 receptor antagonist);
CX-717 and CX-1739 (AMPAkines); ADX-71149,
RG-1578, and RG-7090 (mGluR ligands); ABT-
288, S-38093, and SAR-110894 (histamine H3 R
antagonists); pioglitazone and mitoglitazine (PPAR
agonists); PRX-3140 (serotonin 5-HT4 R agonist); Lu
AE58054, SB-742457, AVN-101, and AVN-211 (sero-
tonin 5-HT6 R antagonists); and cutamesine (sigma-1
receptor agonist). In view of the duration of a clinical
development, in this indication it will take at least five
to six years until one of these compounds will make it
to the market.
DISCLOSURE STATEMENT
Authors’ disclosures available online (http://www.j-
alz.com/disclosures/view.php?id=1428).
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