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

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.

Figure optionsDownload as PowerPoint slide