Chapter 2.

Centrally Actlng Analgeslcs

Allen B. Reitz, Michele C. Jetter, Kenneth D. Wild, and Robert B. Raffa

Drug Discovery Research
The R.W. Johnson Pharmaceutical Research Institute
Spring House, PA 19477-0776

introduction - There continues to be a great need for new agents to lessen the
sensation of pain, especially chronic pain, which is presently undertreated. Several
important developments related to the discovery of new analgesics have emerged
since the last review in Annual Reports in Medicinal Chemistry (1). For example, each
of the major opioid receptor types has been cloned and expressed in cell culture assay
systems adaptable to high-throughput screening. Subtypes of each of these receptors
have been characterized and each is a distinct molecular target for drug discovery.
There has also been a number of significant advances involving a variety of non-opioid
analgesic mechanisms. Further, the central activity of 'peripherally-acting' non-
steroidal antiinflammatory drugs (NSAIDs) and the peripheral action of 'centrally-acting'
opioids have become better appreciated. In the clinical area, alternative routes of
administration such as oral morphine, nasal spray, transdermal patch, spinal
administration and patientcontrolled analgesia (PCA) have become increasingly
utilized, particularly for chronic pain (2). Two noteworthy drugs are an injectable NSAID
(Toradol' ketoralac), which has achieved clinical favor, and Ukram' tramadol HCI a),
the first centrally-acting oral analgesic approved in the U.S. in ten years. The present
chapter covers highlights of the general scientific and patent literature on centrally-
acting analgesics during 1994, with lesser coverage of important findings during 1990-
1993. The reader is also referred to recent comprehensive reviews (3-8) and to the
"Current Research in Analgesia" update series found in Analgesia.

Opioids prevail as the major class of clinically-available centrally-acting analgesics.

All three opioid receptors (p,6 and w) have been shown to be coupled via inhibitory G-
protein (pertussis-toxin sensitive) transduction mechanisms, and have been cloned
and expressed (9-16). The first to be cloned was the mouse 6 opioid receptor (mDOR)
which exhibits &receptor binding selectivity and naloxone-reversible inhibition of
forskolin-stimulated adenylyl cyclase activity when expressed in transfected COS
cells (10). The p and wopioid receptors display sequence homology with mDOR and
hDOR. Generally good correlation has been found between visualization of receptor
mRNA and receptor distribution by autoradiography, suggesting local receptor
synthesis at these sites and receptor transport in cases where mismatches occur (17-
22). The demonstration of opioid receptor mRNA co-localization with neuro-
transmitters helps explain certain non-analgesic opioid characteristics such as effects
on locomotor activity. The relative order of mRNA expression in the ascending and
descending pain pathways has been found to be p > K > 6 (22). Each of the three opioid
receptors have been divided further into subtypes.

y-Aaoni& - Novel pyrrolidinone 2 has been reported as a p-selective agonist (23). All
12 possible stereoisomers were synthesized: the S,S,R,R isomer has high affinity and
good selectivity for p-receptors (ratios of Ki values: dp 250 and 6/p 1060), and in vivo
antinociceptive activity. Remifentanil Q) is a newer member of the fentanil series of
opioid analgesics (24). It is a selective F-opioid ligand with a rapid onset and short
duration of action and is targetted to providing analgesia during anesthesia.
Functionally distinct subtypes of p-opioid receptors have been proposed (25,26). One
mpyright 0 1 QQE by A d e r n l o mss, Inc
ANNUAL REWRTS IN MEDICINAL CHEMISTRY40 1 All rights Of reprOduoUon in 89y form reseN6d.
12 Section I- Central N e m u s System DISeaBe8 Robertson, Ed

subtype (p,)has been associated with antinociception, whereas respiratory depression

(27), constipation (28) and physical dependence (29) have been attributed to the other
&). Meptazinol 0,a synthetic hexahydroazepine derivative, has modest selectivity
for the p, receptor subtype, but also displays significant anticholinergic activity (30).

&Aaonists - A human 6 opioid receptor (hDOR) has been cloned and identified by
sequence homology to other 6 receptors and by its ligand recognition profile (31,32).
BW373U86 @) is a relatively selective 6 agonist which produces antinociception in a
variety of animal models, but was found to produce convulsions in mice and primates
(33-35). SNC80, the (+) enantiomer of & has been reported to be essentially devoid of
convulsive activity (36,37). Compound 6 displays good 6 binding affinity and >2000
fold selectivity relative to the p receptor, making it the most selective non-peptide 6
agonist reported (36). There are at least two 6 receptor subtypes (38-44).
Oligodeoxynucleotide antisense studies suggest that mDOR corresponds to that
pharmacologically classified as S, (43).

- Although some currently-used drugs possess affinity for K-receptors (e.g.,

pentazocine, nalbuphene and butorphanol), their pharmacology includes binding to
other opioid receptor types (e.g. p) or mixed agonist/antagonist properties. K Agonists
described to date appear to have less overall clinical efficacy than p agonists, and
possess a tendency to produce dysphoric or psychotomimetic side effects at high
doses. In preclinical models, K-agonist-induced antinociception is associated with less
respiratory depression, dependence liability and withdrawal signs than traditional p
agonists, although K-agonists have been evaluated clinically and then later withdrawn.
However, the postulated existence of multiple K-receptor binding sites (45) raises the
hope that agents selective for one of these subtypes would be superior (45).

A K agonist has been reported that does not cross the blood-brain barrier, but
does produce analgesia (46,47). Compound displays in vivo antinociceptive activity
and moderate affinity for K receptors, along with reduced liability for K-related side
effects such as motor impairment, sedation, and diuresis (48). Furanylpiperazine is
the optimal member of a related series with in vivo antinociception and selective K
receptor binding (49). Compound LQ displays high affinity K binding with good in vivo
activity (50).
Chap 2 Analgesics Raitz, Jetter. Wild, Raffa 13

Several sets of affinity ligands have been prepared specifically for K receptors (51-
53). Of these, compound 11 and the Senantiomer of compound Lz produced long-
lasting analgesia in mice, suggesting irreversible receptor inactivation (52,53).

LN*R’ R2

“)y
C
u R’=H,@=NCS
14 A
IZR’ = NCS, R ~ H=
.. . - Tramadol binds to opioid receptors and inhibits the neuronal
reuptake of norepinephrine and serotonin (54-57). Tramadol is marketed as a racemic
mixture. The opioid binding and neurotransmitter reuptake inhibition are found
predominantly in the separate enantiomers which interact synergistically in several in
vivo antinociceptive models (58). Aryl-substituted octahydroisoindoles 13 are
structurally related to deshydroxytramadol and were found to have in vivo analgesic
activity (59). trans-Ketone 19 displays significant opioid receptor affinity and in vivo
antinociception, and is relatively devoid of sigma binding (60). The indolic portion of
naltrindole (s) is purportedto play a key role in interaction with the address subsite of
the 6 receptor and is an application of the address-message concept. Further
extension of this approach led to spiro structure which displayed potent 6 in vitro
affinity and in vivo antinociceptive activity (61). lndolic derivatives of 543-
hydroxypheny1)morphans such as fl displayed a >180 fold increased affinity for the 6
receptor (62). Aralkyl ethers of naltrexol were prepared to examine the effect of
additional steric bulk at the &position. The 6a-O-benzyl and the 6p-0-benzyl
compounds had the most potent opioid receptor affinities (63).

N-Oxides of opioids such as tramadol &) have been found to be useful prodrug
derivatives (2,64-66). Delayed systemic availability of the parent analgesic drugs may
allow for less frequent dosing to achieve the same therapeutic effect.
 t!g
Section I - Central N e m u e System Diseases Robertson. Ed

4 4 OH
H

Me
H H
H
l5 lz
The first cyclic peptide analog with mixed p agonist/S antagonist properties was
reported (67). Other constrained and modified peptide derivatives were prepared to
continue probing conformational requirements for opioid receptor binding (68-73).
Polyethyleneglycol (PEG) hybrids of enkephalin analogs were found to produce
prolonged antinociception comparable to morphine (74), and showed increased stability
to metabolic inactivation.

k-Adren-r AaqaiSfS - Compounds with q-adrenoceptor agonist activity are

analgesic in animals and humans, and are expected to have less abuse liability than
opioids (75-79). Three receptor subtypes have been cloned and are termed %, +,,
and G, based on their pharmacology (80,81). The subtypes are also named a&lO,
or,-C2, and wC4, respectively, according to their human chromosomal localization
(82). Correlation of the binding of a large number of or, agonists with antinociceptive
activity in the rat suggests the a, receptor mediates analgesia in that species, but
does not formally rule out an involvement of the other subtypes (83). Compounds
which do not bind to non-adrenergic imidazoline receptors are expected to have fewer
cardiovascular side-effects (84). Structure-activity relationships for %-adrenoceptor
binding have been reviewed (8,85). 4-Substituted imidazoles and 2-substituted
imidazolines continue to be prominent substructures found in many of the reported
ligands (86-88). Compounds LB and Lg bear fused bicyclic rings similar to that found
in brimonidine (UK 14,304), which is presently being evaluated clinically for reduction of
intraocular pressure, another +-mediated effect (86,87,89). 2-Amino-2-oxazoline
derivatives form the basis for an additional series of qadrenoceptor ligands (88). Aryl-
substituted morpholines such as 2.Q are or,-agonists (90). lsothiocyanate 21 was
prepared as an affinity probe for wreceptor binding (91).

. . - Cannabinoid receptors have been identified in the CNS, and they are
:annablnolds
potential targets for non-opioid analgesia (92,93). Human cannabinoid receptor (hCBR)
cDNA has 98% amino acid sequence identity to the rat cDNA (94). The brain
cannabinoid receptor (CB,) belongs to the G-protein family and is believed to inhibit
adenylyl cyclase activity through activation of a Gi protein (95). A second cannabinoid
receptor (CBJ has been cloned and has been termed the 'peripheral cannabinoid
receptor' because of its localization primarily in the imune system (96). The knv overall
chap. 2 Analgesics Reltz. Jetfar, Wfld. Raffa 15

sequence homology (44%) between CB, and Ce, suggests subtype-selective

compounds could be discovered. There is also the possible existence of other
receptor subtypes not detected using conventional screening methods (97). The N42-
hydroxyethy1)amide of arachidonic acid is the putative endogenous ligand for
cannabinoid receptors, and it produces significant antinociception in tests predictive of
clinical efficacy (98,99). Cannabinomimetic compounds produce nonopioid (naloxone-
insensitive) antinociception via spinal or supraspinal sites in rodents, probably through
the CB, receptor (100-102). Cannabinoid receptor affinity paralleled antinociceptive
activity for a series of indene derivatives (e.g.u) of pravadoline (103). 3-Acylpyrrole
a displayed cannabinoid activity comparable to tetrahydrocannabinol (104). A
cannabinoid receptor antagonist has been described (105). The first irreversible
cannabinoid receptor affinity label has been prepared (106).

. . - Epibatidine is a nicotinic cholinergic agonist which produces

potent antinociception that is not blocked by the opioid antagonist nakixone or by
hexamethonium, but is attenuated by pretreatment with the nicotinic cholinergic
receptor antagonist mecamylamine (107,108). Three new chemical syntheses of
epibatidine were reported in 1994, and both enantiomers have been shown to have
antinociceptive activity (109-112).

(R)-(+)-Hyoscyamine m) has antinociceptive activity resulting from an increased

acetylcholine release secondary to antagonism of central muscarinic autoreceptors
(113,114). Related 2-phenoxypropionic acids such as ?1were found to have potent
antinociceptive and cognition-enhancing properties, possibly by antagonizing
presynaptic 4 receptors (114). Additionally, muscarinic agonists such as
produced antinociception (115).

a .
-
Galanin is a 29 to 30 (human) amino acid neuropeptide found in a
variety of peripheral and central tissues (1 16). Galanin depresses nociceptive reflex in
newborn rat spinal cord and is antinociceptive to mechanical stimuli when injected
spinally to rats (117,118). Galanin also potentiates the action of morphine and blocks
the nociceptive effect of substance P and calcionin gene related protein pre- and post-
synaptically (119). The availability of the human cloned receptor now makes galanin a
target for high-throughput screening (120).
 ~ 16 Section I- Centml Nervous System Dlsaases Robertaon. Ed

.. -
The potential of neurokinin receptor antagonists as anti-
nociceptive agents has been reviewed (5). A variety of neurokinin receptor ligands
have been reported (121-137), including pyrrolidine 29 and 4-phenylpiperidine ;Lp.
Compound is a member of a large class of related structures in which the
quinuclidine moiety found in the original non-peptide Substance P antagonists has
been simplified to a piperidine ring bearing pendant aryl substitution (123).

.. - Inhibiting the formation of bradykinin or blocking its action is

expected to produce nonapioid analgesia (7,138,139). Since bradykinin and the
related decapeptide kalliden are generated from precursors (kininogens) by the
proteolytic action of serine proteases (kallikreins), kallikrein inhibitors might also be
useful as analgesics. Bradykinin-induced nociceptive effects are mediated through
cell-surface BK, and BK, G-proteincoupled receptors (140,141). The peptidic brady-
kinin antagonist NPC-567 was tested clinically with disappointing results (139). The
first reported series of non-peptide BK, receptor antagonists was based on
bisphosphonium salts found initially by broad screening, but analgesic evaluation was
not disclosed (142,143).
* .
-
stsin
o
a~
t
n- The CCK antagonist MK-329 was progressed to clinical
trials for chronic pain in patients with advanced pancreatic cancer, but clinical efficacy
was not demonstrated (144).

Me

cr- N
NH

a
. . -
There are many serotonin (5-HT) receptor subtypes (5,145).
Sumatriptan is a putative selective 5-HT,, agonist which is used for the treatment of
migraine headaches (146). Several series of 5-HT3antagonists have been reported,
including which may be useful in antimigraine therapy (147,148).
Dihydropyranopyridinessuch as have SHT,-like agonist activity and are claimed to
prevent cephalic pain, especially migraine (149).

-
osine A a o W Enhancement of adenosine release by morphine suggests a
potential role for adenosine in analgesia (150). A series of adenosine derivatives such
as U displayed good in viw antinociceptive activity, which correlated well with A,
receptor affinity (150).
chap 2 Analgeslcs Reltz. Jettar. Wlld. Raffa 17

--The relief of chronic pain is the goal of medicinal chemistry research in

the area of analgesia. The present availability of human cloned opioid receptor
subtypes allows for the directed synthesis of subtype-selective agents which could
have morphine-like antinociception, but without the abuse liability, sedation, and
respiratory depression that restrict the use of current opioids. Non-opioid analgesics
have the inherent advantage of lacking opioid-related side-effects. As with opioids,
receptor sub-type selective agents, such as for %-adrenoceptor agonists, may provide
the best combination of analgesia relative to limiting side-effects. Testing of compound
libraries in highthroughput screening involving the appropriate cloned receptors or in
vitro assays has enormous potential, and could facilitate the discovery of new
analgesic drugs.

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