Synthesis and nicotinic acetylcholine receptor binding affinities of 2- and 3-isoxazolyl-8-azabicyclo[3.2.1]octanes

Abstract

A series of epiboxidine homologues, 2- and 3-isoxazole substituted 8-azabicyclo[3.2.1]octane derivatives was synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors in [ 3H]cytisine labeled rat brain. The 2β-isoxazolyl-8-azabicyclo[3.2.1]octane 9b ( K i=3 nM) was the most potent compound of the series with a binding affinity twice that of nicotine. The 3β-isoxazolyl-8-azabicyclo[3.2.1]octane 15b ( K i=148 nM) exhibited moderate affinity while the corresponding 2α- and 3α-isomers exhibited micromolar binding affinity.