Matera_2016_Eur.J.Med.Chem_108_392

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 alpha3beta4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of alpha3beta4 affinity and alpha3beta4 vs alpha4beta2 selectivity, although they poorly discriminated the homomeric alpha7 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 = 4.7 nM) for the alpha3beta4 subtype and to an excellent alpha3beta4 vs alpha4beta2 subtype selectivity (806-fold), compound 12 selectively activated the alpha3beta4 nAChR (EC50 = 7.4 muM) while eliciting a negligible response at the alpha7 subtype and no effect at the alpha4beta2 subtype.