Synthesis nicotinic acetylcholine receptor binding in vitro and in vivo pharmacology properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs

摘要

Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (>4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs (>5a–e and >6a–e). All of the analogs had high binding affinity for α4β2*-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound >6b had a Ki = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the α4β2*-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50 = 0.13 μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that >6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders.