Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the ?3?4 nicotinic acetylcholine receptor subtype

We report the design, synthesis and pharmacological screening of a group of analogues of anabaseine 2, a naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following a molecular modeling analysis which suggested the replacement of the pyridine ring of 2 with a 3- substituted benzene ring as a means to gain selectivity for the a3b4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of a3b4 affinity and a3b4 vs a4b2 selectivity, although they poorly discriminated the homomeric a7 subtype. The three analogues 6, 12 and 13 were also evaluated in electrophysiological assays, and 12 [6-(3-iodophenyl)-2,3,4,5- tetrahydropyridine] emerged as a rather interesting nicotinic ligand. Indeed, in addition to a noteworthy affinity (Ki ¼ 4.7 nM) for the a3b4 subtype and to an excellent a3b4 vs a4b2 subtype selectivity (806-fold), compound 12 selectively activated the a3b4 nAChR (EC50 ¼ 7.4 mM) while eliciting a negligible response at the a7 subtype and no effect at the a4b2 subtype