In 1992, John Daly et al. reported the isolation and structure determination of
epibatidine.
Epibatidine's unique structure and its potent
nicotinic agonist activity have had a tremendous impact on
nicotine receptor research. This research has led to a better understanding of the
nicotinic acetylcholine receptor (nAChR) pharmacophore and to
epibatidine analogues with potential as
pharmacotherapies for treating various CNS disorders. In this study, we report the synthesis, receptor binding ([(3)H]
epibatidine and [(125)I]iodoMLA), and in vivo pharmacological properties (mouse tail flick, hot plate,
hypothermia, and spontaneous activity) of a series of 3'-(substituted phenyl)epibatidine analogues (5a-m). Results from these studies have added to the understanding of the nAChR pharmacophore and led to nicotinic partial agonists that may have potential for smoking cessation. All the analogues had affinities for the alpha4beta2 nAChR similar to
epibatidine (1). 3'-(3-Dimethylaminophenyl)epibatidine (5m) has a nicotinic partial agonist pharmacological profile similar to the smoking cessation
drug varenicline. Other analogues are partial agonists with varying degrees of nicotinic functional agonist and antagonist activity. 3'-(3-Aminophenyl)epibatidine (5j) is a more potent functional agonist and antagonist in all tests than
varenicline. 3'-(3-Fluorophenyl)epibatidine and 3'-(3-chlorophenyl)epibatidine (5c and 5e) are more potent than
varenicline when tested as agonists in four pharmacological tests and antagonists when evaluated against
nicotine in the
analgesia hot-plate test.