Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 nicotinic acetylcholine receptor subtype.

摘要: We report the design, synthesis and pharmacological screening of a group analogues anabaseine 2, naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following molecular modeling analysis which suggested replacement pyridine ring 2 with 3-substituted benzene as means to gain selectivity for α3β4 subtype. Overall, from binding experiments, synthesized compounds showed high values affinity vs α4β2 selectivity, although they poorly discriminated homomeric α7 three 6, 12 13 also evaluated in electrophysiological assays, [6-(3-iodophenyl)-2,3,4,5-tetrahydropyridine] emerged rather interesting ligand. Indeed, addition noteworthy (Ki = 4.7 nM) subtype an excellent (806-fold), compound selectively activated (EC50 = 7.4 μM) while eliciting negligible response at no effect