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

Abstract 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 K i  = 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 AD 50  = 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.