Chapter 5. Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology

Chapter 5. Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry and Pharmacology Ian A. McDonald, Nicholas Cosford, Jean-MichelVernier Salk Institute Biotechnology/lndustrialAssociates, La Jolla, CA 92037 lntroduction - In contrast to the immense effort directed towards the design and synthesis of selective muscarinic acetylcholine receptor (mAChR) agonists, nicotinic acetylcholine receptors (nAChR) have attracted very little attention. The pharmacology of nAChRs has been intensively studied, however, and is well summarized in a recent review (1). The current interest in the medicinal chemistry aspects of nAChRs is due, in part, to perceived beneficial effects of nicotine in CNS disorders such as Alzheimer's and Parkinson's diseases (2) and to notable advances in the molecular biology of these receptor complexes. This chapter will review nAChR medicinal chemistry efforts to date and will discuss the future of this field in which the potential to design safe, effective new therapies is closely linked to a growing knowledge of the existence of discrete receptor subtypes and their relationship to physiological disorders. RECFPTOR STRUCTURE hlolecular Biology - nAChRs are pentameric, ligand-gated ion channels belonging to a family of receptor complexes including the glycine (3), 5-HT3 (4) and GABA, (5)receptors. The best characterized are the Torpedo electric organ nAChR and the homologous vertebrate skeletal muscle receptor (6) which are composed of four individual subunits (a1, p, 'y, 6 or E). In neuronal tissue, several genes have been identified that are homologous to muscle nAChR genes. Those coding for proteins with two adjacent cysteine residues at positions 192 and 193 are called a subunits and those that lack them are termed p subunits. Genomic libraries have yielded full length clones for &-a9 and p2-p4 subunits from numerous animal species (7,8). Functional homo-oligomeric receptors (electrophysiology and/or pharmacology) have been observed with a7, a8 and a9 subunits alone (9-12). Hetero-oligomeric receptor complexes assemble when d!, a3 or a4 subunits are separately coexpressed with either p2 or p4 subunits to form a pentameric structure (13-17). The a5 subunit, in combination with a4 or p2 in oocytes gives no conductance signal in voltage clamp and patch clamp electrophysiological experiments. However, when all three subunits are co-expressed, a new nAChR was observed with properties distinctly different from a4P2 (18). Neither the relevence of these recombinant nAChRs to, nor indeed the molecular composition of native human CNS receptors per se, is known with any certainty. Conceivably, endogenous a receptors may exist as homo-oligomeric complexes or might occur in any hetero-oligomeric combination of subunits in combination with other a and p combinations. For example, immunodepletion experiments suggest that chick ciliary ganglia contain a receptor complex which is composed of at least three different subunits - a3, a5 and p4 subunits (19). When chicken neuronal nAChRs are expressed in oocytes, two a4 subunits assemble with three p2 subunits to form a functional receptor complex (20). The Copyright 0 19983 by Aosdemic Ppees.In0

ANNUAL REWRT8 D l MEDICINAL C H E M I S T R Y 4 0

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development of transgenic animal models may help elucidate the physiological roles of specific nAChR subunits. In a recent paper it was reported that transgenic mice lacking the p2 subunit exhibited abnormal avoidance learning behaviour (21).

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M c h R Structural $5- ' nAChRs have been the subject of an enormous number of structural studies over the past two decades. Excellent recent reviews (22-26)illustrate the prominence of the Torpedo ray nAChR in these studies. All nAChR subunits are membrane bound proteins and appear to have four membrane spanning regions, with both amino and carboxyl terminii on the extracellular side. Rapid freezing techniques, coupled with electron microscopy of acetylcholine-treated Torpedo ray membranes, elegantly visualized the gross nAChR pentameric structure (27). Affinity labeling studies have identified a number of amino acid residues in the ligand binding site of the Torpedo receptor complex (23,28). Like other ligand-gated ion channels, nAChRs are believed to be replete with allosteric binding sites (29).An NMR study of the solution structure of a-bungarotoxincomplexed to a small peptide portion of the Torpedo nACHR has been reported (30).Theoretical models of the nAChR binding site have been proposed (31). RECEPTOR AGONISTS Therapeutic Qpportunities - Selective nAChR agonists have great potential as therapeutic agents for a diverse group of central and peripheral nervous system disorders. Based largely on clinical observations with nicotine (2), coupled with a growing understandingof the pharmacology of nAChR agonists, these agents portend therapies for cognitive and attention disorders (32-34),Alzheimer's disease (2,34-39),Parkinson's disease (2,38,40, 41),anxiety (42,43), depression (44), smoking cessation (45),neuroprotection (46-49), schizophrenia (50, 51), analgesia (52,53),Tourette's syndrome (1)and ulcerative colitis

(54).

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Classic nAChR Aaonists and AntagpniStS Early pharmacological characterization of nAChRs relied upon agonists, such as acetylcholine (I),(S)-nicotine (?), arecoline (a), anabaseine (4), DMPP (s), methylcarbamylcholine, lobeline (6) and cytisine (Z);or

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antagonists, such as hexamethonium, decamethonium, mecamylamine (B), d-tubocurarine (S), dihydro-9-erythroidine methyllycaconitine(U),a-bungarotoxin and snake a-toxins, among others (1). A series of recent papers discussed a rapid isolation procedure for ll and reported on the synthesis of several structural analogues (55-57). Although these ligands have been extremely valuable pharmacological tools they appear to have limited therapeutic potential which is probably due to unacceptable side-effects. For example, activation of ganglionic or muscle receptors by nicotine (a) is seriously dose-limiting and severely limits this drug as a candidate for the treatment of CNS disorders (58). One drug (metocurine, a methoxy derivative of 9), however, is used clinically as a muscle relaxant (59), and a second (6) is in Phase I1 clinical trials for smoking cessation (60). Furthermore, Z is continuing to be evaluated and has shown good activity in pharmacological models of

(m),

learning and memory (61) and analgesia (62), suggesting that nAChRs may play a role in the modulation of these processes. The growing understanding of the multiple nAChR complexes clearly points to the need for subtype selective ligands. In an important paper it was reported that 1,2,15 and L exert differential agonist effects on the recombinant receptor complexes a2P2, a3p2, a4P2, a2P4, a3P4 and a4P4, indicating that the discovery of such selective compounds is conceptually attainable (63). a nAChR Aa-onists. Recent Advances - Since the report (64) in 1992 that epibatidine (U), 7-azanorbornane analogue of nicotine, possessed extraordinary analgesic properties and the demonstration in early 1994 that 12 was an exquisitely potent nAChR agonist (53, 65), many groups turned to the synthesis of this interesting molecule. Syntheses of racemic la (66-73), enantiomerically pure forms (74-76) and the derivatives to I5 appeared (76). Interestingly, removal of the chlorine atom in (i.e. B)had no effect on binding potency. The absolute configuration of l.2 was determined to be 1R, 2R, 4 s (75). Both enantiomers of j.2 possess potent analgesic properties (77) and bind to [3H]-2sites in rat brain with the same affinity (Ki = 55 pM). Since the analgesic effect is blocked by 8, nAChRs are strongly implicated in the mechanism of action. Epibatidine however, is a potent toxin (isolated

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from the skin of a poisonous frog) and has an extremely narrow therapeutic index. The challenge is to separate the toxicity from its analgesic effect; whether both effects are mediated through nAChRs remains to be established.

a R=CI R=H

14 R=CH3 R=l

Another well known toxin, (+)-anatoxha (N), produced by the fresh water cyanobacterium Anabaena flos aqua, has attracted considerable chemical and biological interest. In four functional assays (78), 16 was found to be more potent than either 1 or 2. Compound 16 potently stimulated stably expressed, recombinant a4p2 and a7 nAChRs, stimulated the release of (1) from hippocampal synaptosomes, and activated abungarotoxin-sensitive nAChRs using patch clamp techniques. Analogues to U, in which the side chain of 16 has been modified, have been prepared and studied (79). Working with a series of 21 anatoxin analogues, a QSAR study led to clustering models with reasonable predictive properties (80). Conformationally biased @Q) or constrained to 23) analogues were reported (81, 82). Compound ap was significantly less active than 16; no biological data were furnished for 2l-a.

=

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H3C

2 l 2,7-unsaturation 22 4,5-unsaturation, cis-ring fusion

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0 7

ZI 4,5-unsaturation, trans-ring fusion

A synthesis of ferruginine (24) was reported (83) and this product and analogues (e.g. were claimed as nAChR agonists for the treatment of neurodegenerative diseases (84, 85). The binding affinities of a series of isoarecolones and arecolones for nAChRs and

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(a n)

mAChRs were reported (86). The most selective compounds and in each series had K, (nAChR) values of 26 nM and 6 nM, respectively, with selectivity relative to mAChR binding of >195 and 336, respectively. Although nicotine (2) has been known to chemists for decades, surprisingly little systematic SAR study has been undertaken with this small molecule. The synthesis and binding properties of a series of pyrrolidine-substitutednicotine analogues was reported (87). An important observation was that the trans 5-P-CH3derivative (29,K, = 35 nM) was 5 = 1.2 pM). The same laboratory significantly more potent than the cis 5-a-epimer (N, claimed in a patent application (88) a vast number of structures related to which has potent affinity for the nAChR (K, = 0.2 nM; [3H]-Z). The Klinked pyrrolidine K, = 49 nM) has also appeared in the patent literature (88). A high affinity, irreversible nAChR ligand Ki = 70 nM) was described (90).

(a)

(a;

(a,

R4

26

29 p-Isomer 3Q a-Isomer

P

P

(+)-a (-)-a,

The conformationally restrained isoquinoline was reported to possess antinociceptive properties in vivo but this compound had no appreciable affinity for nAChRs in binding experiments (91). In contrast, was a somewhat less potent antinociceptive agent, but bound to nAChRs with modest affinity. The (+)-isomer had the same relative (the natural form), Other tricyclic nicotine analogues to X) stereochemistry as (S)-(-)-Z have been previously described; 35 and 36 had no appreciable biological activity (92, 93). however, which encompasses structural features of 2 and 16,was very The compound, potent in binding (lC5,, = 5 nM) and functional assays (94).

(s

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Robertaan. Ed.

OCH3

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S The anabaseine analogues S to 4p demonstrate the potential of designing selective nAChR agonists. These novel structural variants were found to have significant effects on nAChR receptor binding and functional properties. For example, whereas 4 was shown to be a strong partial agonist at a4p2 nAChRs expressed in oocytes, a 4 pwere were more potent agonists at a7 than 4. The K, values weak agonists. However, S-4.Q from binding studies with [3H]-L(putatively indicating affinity for a4P2 nAChRs) and ['251]-BTX (1x7) were in accord with these observations (95). The pharmacology of these molecules is no less interesting. They were active in a model of passive avoidance in bilaterally nucleus basalis-lesioned rats, but were less potent than 2 or 4 (96). One compound (S)was shown to facilitate eyeblink classical conditioning which is believed to reflect activation of the septohippocampal cholinergic system (97). Finally, it was reported that S elicits cytoprotective activity in NGF-sensitive neuronal populations (98). ABT 418 (41)further exemplifies the therapeutic potential of nAChR agonists which show selectivity for central receptor subtypes. This isoxazole derivative displaces [3H]-Zwith a K, = 4.2 nM (equipotent with 2) and is postulated to show selectivity for a4P2 receptors (99). The (S)-enantiomer, like (S)-(2),is about 10-fold more potent than the (R)-isomer. Extensive SAR studies have been reported (99-101). Although 41 does not appear to have

a

R=H R=PCH3 R=aCH3

CH3 been studied in cells expressing functionally active, recombinant nAChR subunits, in PC12 cells patch clamp studies have demonstrated potent agonist activity (102). Extensive in vivo experiments clearly indicate that fi has both cognition-enhancing and anxiolytic properties (102) which are convincingly mediated through a nAChR mechanism (blocked by a). Its

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poor pharmacokinetic profile after oral administration, but excellent transdermal properties, led to the decision to develop this promising compound as a patch for the treatment of AD. In an apparent attempt to address the bioavailability issue (1Ol), the 5’-methyl-substituted derivatives 42 and (K, = 71 nM and 5 pM respectively) were prepared; in vifm half lives of 42 and however, were not greatly improved.

a,

P h a w o p h o r e Modeliu - Attempts to develop nAChR agonisVantagonist pharmacophores have been reported on several occasions. A conformational analysis approach led to the proposal that one of the key elements in the binding of ligands to the nAChR is a hydrogen bond between a receptor hydrogen donor group and an acceptor group in the ligand and is formed 5.9 A from the positively charged aliphatic nitrogen atom (103). In contrast, acetylcholine adopts a more compact conformation in the active site of the mAChR such that this distance is reduced to 4.4 A. A more elaborate nAChR model, which was developed by distance geometry methods, was in basic agreement with thess predictions (104).To date, however, these models out of necessity have considered the nAChR as a single complex. As subtype selective ligands are developed, more refined models will be forthcoming. Reers and Reich pharrnacophore (103

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2

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Conclusion - The therapeutic potential of selective nAChR agonists today is reflective of the

situation of 5-HT medicinal chemistry a decade ago. There are multiple receptor subtypes, it is clearly possible to design selective agonists (and antagonists), an old drug &) is in Phase II clinical trials and the first of the newer drugs (41) has recently entered the clinic. Furthermore, there is a growing understanding of the physiological and pharmacological effects of drugs acting at nAChRs (105-108). The challenge today lies on several fronts. First, is the localization and characterization of endogenous receptor subtypes, and the need to demonstrate the link between receptor subtypes and particular diseases or physiologicalfunctions. Second, is the development of cell-based functional assays in which physiologically relevant, recombinant receptor complexes are used for drug screening and characterization. These multirneric receptor complexes present a significantly greater challenge to molecular and cellular biologists than the G-protein linked serotonin receptors. Finally, structure-activity relationship studies need to be developed for each receptor subtype and therapeutically useful compounds must be designed and synthesized. This short review has focused primarily on the design of ligands interacting at the acetylcholine binding site; clearly future drug development will consider both competitive and allosteric binding sites.

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