Novel 3-Pyridyl Ethers with Subnanomolar Affinity for Central Neuronal Nicotinic Acetylcholine Receptors

Abstract

Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

Differential α4(+)/(−)β2 Agonist-binding Site Contributions to α4β2 Nicotinic Acetylcholine Receptor Function within and between Isoforms

“…A-85380 demonstrates an unusually high degree of agonist selectivity between HS and LS isoform ␣4␤2-nAChR (24,36,45). In response to acute A-85380 stimulation, the HSP ␤2HQT position 1 construct generated a clearly biphasic CRC with an ϳ1:1 distribution of HS and LS components (Fig.…”

The Uniqueα4(+)/(−)α4 Agonist Binding Site in (α4)3(β2)2Subtype Nicotinic Acetylcholine Receptors Permits Differential Agonist Desensitization Pharmacology versus the (α4)2(β2)3Subtype

“…In this study, we sought to use more discriminating ligands to dissect the roles played by a4(1)/ (2)b2 and a4(1)/(2)a4 interfaces in HS and/or LS a4b2-nAChR isoforms. We investigated activation and desensitization of receptors in response to acetylcholine (ACh) and to two highly HS-versus LS-selective nicotinic agonists that might better discriminate between a4b2-nAChR isoforms: A-85380 [3-(2(S)-azetidinylmethoxy)pyridine] (Abreo et al, 1996) and sazetidine-A [6-(5-(((S)-azetidin-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol; henceforth abbreviated as Saz-A] (Xiao et al, 2006). We report that HS-phase a4b2-nAChR responses can be selectively inactivated by low concentrations of either ligand, while leaving LS-phase responses in a state that can still be activated by acute agonist application.…”

Structure-activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency

“…Recently, a number of structure-activity studies have appeared relating chemical structure to both receptor binding affinity, employing [ logical potency. Among the nicotine analogs studied were 3′-, 4′-, and 5′- [Lin et al, 1994] substituted, N′-substituted [Abood et al, 1993;Glassco et al, 1996], pyrrolidine modified and 6-substituted [Dukat et al, 1996], and 3-pyridyl ethers with subnanomolar affinities for nicotinic cholinergic receptors [Abreo et al, 1996].…”