Nicotinic agonist

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at

nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity
for nicotine.

Examples include nicotine (by definition), acetylcholine (the endogenous agonist

of nAChRs), choline, epibatidine, lobeline, varenicline and cytisine.

History

Chemical structure of ABT-418

Nicotine has been known for centuries for its intoxicating effect. It was first
isolated in 1828 from the tobacco plant by German chemists, Posselt and Reimann.
[1]

The discovery of positive effects from nicotine on animal memory was discovered
by in vivo researches in the middle of the 1980s. Those researches led to a new era
in studies of nicotinic acetylcholine receptor (nAChR) and their stimulation but
until then the focus had mainly been on nicotine addiction. [2][3] The development of
nAChR agonists began in the early 1990s after the discovery of nicotine’s positive
effects. Some research showed a possible therapy option in preclinical researches.
ABT-418 was one of the first in a series of nAChR agonists and it was designed by
Abbott Labs.[3] ABT-418 showed significant increase of delayed matching-to-
sample (DMTS) performance in matured Macaque apes of different species and
sex.[4] ABT-418 has also been examined as a possible treatment to Alzheimer’s
disease, Parkinson’s disease and attention-deficit hyperactivity disorder: those
experiments showed positive outcomes.[3]

One of the first nAChR active compounds, besides nicotine, that was marketed as a
drug was galantamine, a plant alkaloid that works as a weak cholinesterase
inhibitor (IC50=5µM) as well as an allosteric sensitizer for nAChRs (EC50=50
nM).[5]
Nicotinic acetylcholine receptors and their signaling system

Nicotinic acetylcholine receptor classification

Signaling system

In the human nervous system nicotinic cholinergic signals are extended throughout
the system, where the neurotransmitter acetylcholine (ACh) plays a key role in
activating ligand-gated ion channels.[6] The cholinergic system is a vital nervous
pathway, where cholinergic neurons synthesize, store and release the
neurotransmitter ACh. The main receptors that convert the ACh messages are the
cholinergic muscarinic acetylcholine receptors, neuronal and muscular nAChRs.
When looking back at evolutionary history, ACh is considered to be the oldest
transmitter molecule and became present before the nervous cell. In the nervous
system cholinergic stimulation mediated through nAChRs controls pathways such
as release of transmitters and cell sensitivity, which can influence physiological
activity including sleep, anxiety, processing of pain and cognitive functions.[7]

Nicotinic acetylcholine receptors

nAChRs are cholinergic receptors found in the central nervous system (CNS),
peripheral nervous systems (PNS) and skeletal muscles, these receptors are ligand-
gated ion channels with binding sites for acetylcholine and other molecules. When
ACh or other agonists bind to the receptors it stabilizes the open state of the ion
channel allowing influx of cations such as potassium, calcium and sodium ions.
The nAChRs are made up by different subunits which determine the quaternary
structure of the receptor, those subunits are α subunits (α1−α10), β subunits (β1−β4),
one δ subunits, one γ subunit and one ε subunit. nAChRs can be either heteromeric
or homomeric. The heteromeric receptors found in the central nervous system are
made up by two α subunits and three β subunits with the binding site at the
interface of α and the adjacent subunit. These receptors contain two binding sites
per receptor and have different affinity for chemicals based on the composition of
subunits. Both binding sites work together and thus, both sites need to be occupied
with a nAChR agonist so that channel activation can take place. [8] nAChRs
containing α2−α6 and β2−β4 subunits have been shown to have higher affinity for
ACh than other receptors. Homomeric receptors contain 5 identical subunits, they
have 5 binding sites located at the interface between two adjacent subunits. In the
year 2000 two homomeric receptors had been identified in humans, the α 7 and α8
receptors.[7][9][10][11]

Mechanism of Action

Two different subtypes of nicotinic acetylcholine receptors

Binding site

There are two binding sites on heteromeric nAChRs; to stabilize the open form of
nAChRs, both binding sites must be occupied by agonist, such as nicotine or ACh.
[10]

The ACh binding site of nAChR is made up by six loops, termed A–F. The A, B
and C loops of the binding site are part of the α subunit and are the principal
components of the binding site. The adjacent subunit to the α subunit (γ, δ, ε or β)
contains the D, E and F loops.[10]

α4β2 receptor agonists

α4β2 nAChRs contain two α4 subunits and three β2 subunits, therefore it has two
binding sites for ACh and other agonists. α4β2 nAChRs account for approximately
90% of the nAChRs in the human brain and when chronically exposed to nicotine
or other nicotine agonists leads to increase in density of α 4β2 receptors which is the
opposite of what usually happens when other receptors are chronically exposed to
their agonists. The α4β2 receptor has been widely studied in regards to Alzheimer’s
disease as well as for nicotine dependence and in 2009 several drugs are on the
market that target the α4β2 nAChR specifically.[12][13]

α7 receptor agonists

α7 receptors are homomeric neuronal acetylcholine receptors consisting of five α 7

subunits and has five ACh binding sites. Abnormality in the α 7 receptors
expression have been reported to influence progression of diseases such as
Alzheimer’s disease and schizophrenia. The α7 are not believed to have as much
affinity for nicotine as the heteromeric receptor but instead they have shown more
affinity for alpha bungarotoxin which is a nicotinic antagonist found in venom of
some snakes. Targeting of α7 receptors is therefore thought to be useful in
treatment of Alzheimer’s disease and schizophrenia.[8][14]

Muscle type receptor agonists

nAChR are found in the neuromuscular junction on skeletal muscles. Two different
receptors have been found, one of which has primarily been found in adults
contains two α1 subunits, one β1, one ε and one δ, the other one has been found in
fetuses and contains γ subunit instead of the ε subunit. The nAChRs take part in the
depolarization of the muscular endplate by increasing cation permeability leading
to contraction of skeletal muscles.[15] The nAChRs found in the skeletal muscle
system have two ACh binding sites, one of which is found at the interface between
α1 and δ subunits while the other one is found at the interface between α1 and γ or ε
subunits. Among nAChR antagonists designed specifically for the neuromuscular
system are nerve gases and other poisons designed for quick kill either of humans
and other animals or insects.[11]

Binding

ACh binds to nAChR because of charge difference between the molecule and the
surface of the receptor. When binding to nAChR ACh fits into a binding pocket
shaped by loops A, B and C which belong to α subunit and the adjacent subunit.
When ACh is fitted into the binding pocket the loops of the nAChR undergo
movement that leads to a coordination of the ACh molecule in the pocket
enhancing the chemical bonds between the molecule and the receptor. After
movement of the loops that belong to α subunit it’s sometimes possible for the
ACh molecule to form a bond, e.g. salt bridge, to the adjacent subunit enhancing
the bonds between the receptor and ACh even further.[16]

Drug design

Drugs that influence nAChRs can be agonists, partial agonists or antagonists.

Agonists, e.g. nicotine, can however act as depolarizing agents when encountered
to nAChRs for some time (seconds or minutes, depending on concentration and
nAChR subtype), chronic exposure to agonist can also lead to long lasting
functional deactivation because of rapid and persistent desensitization. Partial
nAChR agonists have been studied since they seem to be helpful in smoking
cessation. The partial agonists are believed to bind to the nAChRs and stimulate
the release of dopamine in smaller portions than the agonists and therefore
compensate for the absence of nicotine.[17]
The lack of specificity among some of the nicotinic agonists is well known and is a
potential problem when using them to treat illnesses that require targeting a
specific subtype of nAChRs. Among these nonspecific agonists are for example
ACh, nicotine and epibatidine that all target more than one subtype of nAChRs.[18]

Pharmacophore
Chemical structure of nicotine

The development of nAChR agonist pharmacophore started in 1970 when it was

proposed that the binding of the agonists to a receptor was dependent on a
positively charged nitrogen atom and a hydrogen bond forming from carbonyl
oxygen atom in acetylcholine or a nitrogen atom in (S)-nicotine. Since then it has
been shown that a cationic center, atoms that are electronegative and able to form
hydrogen bonds along with the center of the pyridine ring in (S)-nicotine are
favorable. Stereochemistry is a part of the pharmacophore as is clearly seen with
(S)- and (R)- nicotine where the (S)-enantiomer is 10-100 times more potent. The
azabicyclic ring of epibatidine is another example of favorable steric interactions to
the receptors. It has been suggested that a specific internitrogen distance, N +-N, is
important for agonist affinity but debate has arisen over its influence. A newer
theory is that a distance of 7-8 Å between points that complement the protonated
nitrogen atom and hydrogen bond acceptor will enhance the potency. Low
electronic density close to the protonated nitrogen and higher electron density close
to the pyridine ring is favored in protonated nicotine ligands containing pyridine
ring. In later years researchers have taken more interest in the α 7 and α4β2 subtype
receptors in drug development to treat nicotine dependence and cognitive
impairment such as Alzheimer’s.[19]

Structure-activity relationships

Structure-activity relationships: Muscle nAChR agonists

Various models have been run where the affinity of nAChR agonists to the
receptor subtype are tested to help identify the molecules, groups and steric
conformation that are vital to greater affinity. By using a nAChR muscle receptor
subtype (α1)2β1δγ model the following results were obtained:

anatoxin > epibatidine > acetylcholine > DMPP >> cytisine > pyrantel >
nicotine > coniine > tubocurare > lobeline,

where anatoxin had the highest activity efficacy and tubocurare the lowest.
Acetylcholine on the other hand induced a much longer opening time of the
receptor though anatoxin is more potent. The results suggest that anatoxin
derivatives would be helpful in understanding structure-activity relationships
(SAR) for muscle nAChRs.[20]

Succinylcholine chloride, which is a drug that’s already on the market, is a

bischoline ester and a short acting muscle relaxant. Bischoline esters are
compounds that can act as a competitive agonist on muscle type nAChRs and have
been used in SAR studies. In a Torpedo (α1)2β1δγ nAChR model it was
demonstrated that the potency of bischoline ester agonists is dependent on the
chain length as potency increases with longer chains. Efficacy seems to be
independent of chain length since the highest efficacy is seen in bischoline esters
with four to seven CH
2 units and is lower for both fewer CH
2 units and more. [21]

Structure-activity relationships: α4β2 nAChR agonists

Pyridin cyclopropan derivatives

Combination of structural elements of ACh and nicotine as well as reducing the

conformational flexibility by using a cyclopropane ring has led to the discovery of
potent and selective α4β2 nAChR ligands. The modulation of three structural
elements, the linker, substitution on the amino group and the pyridine ring can be
used to determine the influence on potency and selectivity of the ligands. Factors
that decrease the binding are steric hindrance on the amino group and linkers that
are saturated/unsaturated carbon chains. Short-chained ether linkers are preferred.
Beneficial effects on the binding is seen with substitution on the pyridine ring both
mono- and disubstitution with halogens among other groups. Substitution on the
amino group with three different amides increased the binding affinity where
methylamide had the highest binding. Lower binding in the other substituted
amides was explained by steric hindrance or lack of a methyl group resulting in
loss of hydrophobic interaction. Stereochemistry of pyridine nitrogen and/or the
pyridine ring and its stereoelectronic effects has a subtle beneficial effect on the
binding to the α4β2 nAChR. Thus it was shown that a pyridyl ether ligand with
bromo substitution on the pyridine and metylatedamide on the amino group had the
highest potency.[22]
 Structure-activity relationships: α7 nAChR agonists

SEN12333/WAY-317538

Structure activity relationship model for

α7 agonists

The search for selective and potent α7 nAChR agonists has produced a series of
compounds that have good potential as drug candidates. One such search produced
SEN12333/WAY-317538 among other compounds that have desirable
pharmacokinetic profiles and are selective of α7 nAChRs over α1, α3 and α4β2
nAChRs. Structure activity relationships for these compounds have been proposed.
[14]
The optimal pharmacophore of α7 nAChR agonist is made of three parts. There
is a basic moiety connected to a carbon chain linked to an aromatic moiety by an
amide bridge. The amide bridge can be inverted without affecting the potency of
the agonist. A biaryl group shows more potency than a monoaryl group as the
aromatic moiety and substitution at position 2 on the later aryl group will further
increase the potency. Potency is higher for agonists with H + donor/acceptor on the
later aryl group on the biaryl group. A high number of hydrogen bond acceptors
could decrease permeability across the blood–brain barrier (BBB) do to the polar
surface area and needs to be taken into account when designing agonists to target
α7 nAChRs.[14]

Various cyclic amine groups can act as the basic moiety and potency stays
relatively unchanged for example aryl piperazine, piperidine and morpholine. An
acyclic tertiary amine is tolerated as the basic moiety but larger steric groups are
less tolerated.[14]

Many derivatives of quinuclidine such as quinuclidine amide are known to be α7

nAChR agonists. SAR studies for quinuclidine amide have identified factors that
are affecting the potency and affinity of these agonists. Para substitution on the
quinuclidine ring and the 3-(R) configuration in the stereochemistry is favored.
Enhanced activity is observed when a 5 membered ring is fused to aromatic
moiety. Further enhancement is seen when the fused ring is able to supply electron
resonance to the amide carbonyl whereas the activity will diminish when the fused
ring contains a hydrogen bond donating atom. The rigidity of quinuclidine and the
orthogonal orientation of the nitrogen bridge in relations to the amide carbonyl
group is presumed important for the optimal binding. The stability of some of the
more potent quinuclidine amide derivatives in rat in vitro models have been low
however by adding a methyl group to position 2 on the quinuclidine ring the
stability has increased greatly.[23]

Drug development

The development of nicotinic acetylcholine receptor agonists began in the early

1990s after the discovery of nicotine’s positive effects on animal memory. [2][3] The
development of nicotinic acetylcholine receptor agonists has come a long way
since then. The nicotinic acetylcholine receptor agonist are gaining increasing
attention as drug candidates for multiple central nervous system disorders such as
Alzheimer's disease, schizophrenia, attention-deficit hyperactivity disorder
(ADHD) and nicotine addiction.[24][25] Nicotinic acetylcholine receptors are
receptors found in the central nervous system, the peripheral nervous systems and
skeletal muscles. They are ligand-gated ion channels with binding sites for
acetylcholine as well as other agonists. When agonists bind to a receptor it
stabilizes the open state of the ion channel allowing influx of cations.[8]

In 2009 there were at least five drugs on the market that affect the nicotinic
acetylcholine receptors.

Quinuclidine derivatives

Quinuclidine Carbamates Quinuclidine Amides Quinuclidine Ethers

Products of nicotinic agonist

 Pharmace Pharmacod
Active Product Chemical Therape
utical ynamic Structure
ingredient name name utic use
form properties

7,8,9,10- Partial
tetrahydro- agonist of Treatme
Film the nicotinic nt of
Vareniclin Champix, 6,10-methano-
6H- coated acetylcholin tobacco
e tartrate Chantix
pyrazino[2,3-h] tablet e receptor, depende
[3]benzazepine[ subtype nce[26]
25]
α4β2[26]
Cholinestera Treatme
4a,5,9,10,11,12
Sustained se inhibitor nt of
Reminyl, -hexahydro-3-
release and a dementi
Galantam Nivalin, methoxy-11-
capsule, noncompetat a caused
ine Razadyne methyl-6H-
film ive agonist by
hydrobro and benzofuro[3a,3,
coated of the Alzheim
mide Razadyn 2-ef][2]-
tablet, oral nicotinic er's
ER benzazepin-6-
solution acetylcholin disease[28
ol[27]
e receptor[3] ]

Nicorette,
Nicotinell,
Transderm
Niquitin, Agonist of
al patch,
Boots the nicotinic Treatme
3-[(2S)-1- gum,
NicAssist, receptor,[29] nt of
methylpyrrolidi inhaler,
Nicotine Commit, both tobacco
ne-2- nasal
Habitrol, Ganglion depende
yl]pyridine spray,
Nicoderm type and nce[31]
lozenge,
CQ, α 4 β2[30]
microtab
Nicotrol,
Thrive
2-
Treatme
[(aminocarbony
Intraocula Cholinergic nt of
Carbachol Miostat l)oxy]-N,N,N-
r solution agonist[32] glaucom
trimethylethana
a
minium
2,2'-[(1,4-
Suxameth
Anectine, dioxobutane- Intravenou Depolarizin Short
onium
Quelicin 1,4- s or g acting
chloride
Suxameth diyl)bis(oxy)]bi intramusc neuromuscul muscle
(Succinylc
onium s(N,N,N- ular ar blocking relaxant[3
holine
Chloride trimethylethana injection agent[33] 4]

chloride)
minium)
 2-(6-
Agonist of
chloropyridin-
Epibatidi the nicotinic Not used
Not listed 3-yl)-7- Not listed
ne acetylcholin as a drug
azabicyclo[2.2.
e receptor[35]
1]heptane

Other nicotinic agonists, albeit generally with limited clinical use, include:

 lobeline, an agonist on Ganglion type nicotinic receptors and also affects

sensory nerve terminals[30]
 epibatidine, and agonist on Ganglion type, α4β2 and α7 receptors.[30]
 decamethonium causes depolarization block on muscle type receptors,
similarly to suxamethonium[30]

Nicotinic versus muscarinic activity

Comparison of cholinergic agonists[36]

Receptor specificity Hydrolysis by
Substance Comments
Muscarinic Nicotinic acetylcholinesterase
Choline +++ +++ ++ Essential nutrient
Acetylcholine +++ +++ +++ Endogenous ligand
Used in the treatment of
Carbachol ++ +++ -
glaucoma
Methacholine +++ + ++
Used in bladder and
Bethanechol +++ - -
gastrointestinal hypotonia.
Natural alkaloid found in
Muscarine +++ - - certain mushrooms. Cause
of mushroom poisoning
Natural alkaloid found in
Nicotine - +++ -
the tobacco plant.
Pilocarpine ++ - - Used in glaucoma
Oxotremorine ++ - -

Current status

Currently nicotine receptor agonist research and drug designing is aimed for
treatment of multiple diseases and disorders of the CNS.
Targacept has four drug candidates that are in clinical trials; AZD3480 (TC-1734)
for ADHD which is currently in phase II clinical trials and AZD1446 (TC-6683)
for Alzheimers disease in collaboration with AstraZeneca, TC-5619 for cognitive
dysfunctions in schizophrenia and TC-5214 as an augmentation treatment for
major depressive disorder (MDD) in subjects who did not respond adequately to
first-line treatment with citalopram hydrobromide.[37]

Memory pharmaceuticals with its partner Roche has one drug candidate, MEM
3454 (RG3487), a partial agonist of the nicotinic α7 receptor, for Alzheimers
disease.[38][39]

Abbott Laboratories in partnership with NeuroSearch have two drug candidates in

clinical trials, ABT-894, a selective α4β2 nicotine receptor agonist, for ADHD and
ABT-560, a neuronal nicotinic receptor modulator, which was selected by Abbott
in 2006 as a new development candidate for cognitive dysfunctions.[40]

EnVivo pharmaceuticals has one drug candidate in clinical trials, EVP-6124, a

selective α7 nicotine receptor agonist for Alzheimer’s disease and schizophrenia
and one follow-up compound, EVP-4473, that has successfully completed pre-
clinical development.[41]

See also

 Nicotinic acetylcholine receptor

 Agonist
 Parasympathomimetic drug
 Muscarinic acetylcholine receptor
 Nicotinic antagonist