Improving the nicotinic pharmacophore with a series of (isoxazole)methylene-1-azacyclic compounds: Synthesis, structure-activity relationship, and molecular modeling

A series of (isoxazole)methylene-1-azacyclic compounds was prepared. The co mpounds were tested for affinity to central nicotinic acetylcholine recepto rs (nAChRs) and central muscarinic receptors. The compounds covered a broad range of affinities for the nAChRs (IC50 = 0.32 to >1000 nM), with selecti vities for the nAChRs over the muscarinic receptors in the range of 3-183. The high-affinity compound (Z)-26 (3-(4-methyl-5-isoxazolyl)methylene-1-aza bicyclo-[2.2.2]octane, IC50 = 3.2 nM) having only one energy minimum was us ed as the reference structure in a computational study. This ligand has ena bled definition of an important distance parameter, and the existence of th is parameter was supported by showing that other potent nicotinic ligands ( for example, nicotine and epibatidine) fit the model.