Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3β4 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 alpha 3 beta 4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of alpha 3 beta 4 affinity and alpha 3 beta 4 vs alpha 3 beta 4 selectivity, although they poorly discriminated the homomeric alpha 7 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 note-worthy affinity (K-i = 4.7 nM) for the alpha 3 beta 4 subtype and to an excellent alpha 3 beta 4 vs alpha 3 beta 4 subtype selectivity (806 -fold), compound 12 selectively activated the alpha 3 beta 4 nAChR (EC50 = 7.4 mu M) while eliciting a negligible response at the alpha 7 subtype and no effect at the alpha 3 beta 4 subtype. (C) 2015 Elsevier Masson SAS. All rights reserved.