Synthesis and binding affinity at α4β2 and α7 nicotinic acetylcholine receptors of new analogs of epibatidine and epiboxidine containing the 7-azabicyclo[2.2.1]hept-2-ene ring system

The structural analogs of epibatidine and epiboxidine (±)-10–(±)-17, characterized by the 7-azabicylo[2.2.1]hept-2-ene ring, were prepared taking advantage of Pd-catalyzed cross-coupling reactions. The compounds were assayed for binding affinity at neuronal α4β2 and α7 nicotinic acetylcholine receptor subtypes. 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 α4β2 and α7 neuronal nicotinic receptors (nAChRs). The set of 3-pyridinyl derivatives (±)-10, (±)-11 and (±)-12 exhibited an affinity for the α4β2 nAChR subtype in the subnanomolar range (Ki values of 0.20, 0.40 and 0.50nM, respectively) and behaved as α4β2 versus α7 subtype selective ligands. Interestingly, the epiboxidine-related dimethylammonium iodide (±)-17, which retained a good affinity for the α4β2 nAChR (Ki=13.30nM), tightly bound also to the α7 subtype (Ki=1.60nM), thus displaying a reversal of the affinity trend among the reference and new nicotinic ligands under investigation.