Synthesis, nicotinic acetylcholine receptor binding, and pharmacological properties of 3′-(substituted phenyl)deschloroepibatidine analogs

Abstract

A series of 3′-(substituted phenyl)deschloroepibatidine analogs ( 5a– j) were synthesized. The α4β2 ∗ and α7 nicotinic acetylcholine receptor (nAChR) binding properties and functional activity in the tail-flick, hot-plate, locomotor, and body temperature tests in mice of 5a– j were compared to those of the nAChR agonist, nicotine ( 1), epibatidine ( 4), and deschloroepibatidine ( 13), the partial agonist, varenicline ( 3), and the antagonist 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs ( 7a– j). Unlike epibatidine and deschloroepibatidine, which are potent agonists in the tail-flick test, 5a– k show no or very low antinociceptive activity in the tail-flick or hot-plate test. However, they are potent antagonists in nicotine-induced antinociception in the tail-flick test, but weaker than the corresponding 2′-fluoro-3′-(substituted phenyl)deschloroepibatidines.