Dallanoce_2012_Bioorg.Med.Chem.Lett_22_829

A group of novel racemic nicotinic ligands structurally related to epibatidine or epiboxidine [(+/-)-10-(+/-)-17] was synthesized through a palladium-catalyzed cross-coupling between the appropriate vinyl triflate and a range of organometallic heterocycles. The target compounds were evaluated for binding affinity at the alpha4beta2 and alpha7 neuronal nicotinic receptors (nAChRs). The set of 3-pyridinyl derivatives (+/-)-10, (+/-)-11 and (+/-)-12 exhibited an affinity for the alpha4beta2 nAChR subtype in the subnanomolar range (K(i) values of 0.20, 0.40 and 0.50nM, respectively) and behaved as alpha4beta2 versus alpha7 subtype selective ligands. Interestingly, the epiboxidine-related dimethylammonium iodide (+/-)-17, which retained a good affinity for the alpha4beta2 nAChR (K(i)=13.30nM), tightly bound also to the alpha7 subtype (K(i)=1.60nM), thus displaying a reversal of the affinity trend among the reference and new nicotinic ligands under investigation.