NOVEL 3-PYRIDYL ETHERS WITH SUBNANOMOLAR AFFINITY FOR CENTRAL NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTORS

Recent evidence indicating the therapeutic potential of cholinergic ch annel modulators for the treatment of central nervous system (CNS) dis orders as well as the diversity of brain neuronal nicotinic acetylchol ine receptors (nAChRs) have suggested an opportunity to develop subtyp e-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-py ridyl ether compounds which possess subnanomolar affinity for brain nA ChRs and differentially activate subtypes of neuronal nAChRs. The synt hesis 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 [H-3]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha 4 beta 2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selecti vity to stimulate ion flux at human alpha 4 beta 2 nAChR subtype compa red to human ganglionic type nAChRs. Computational studies indicate th at a reasonable superposition of a low energy conformer of 4a with (S) -nicotine and (-)-epibatidine can be achieved.