Epiboxidine and novel-related analogues: A convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Racemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal α4β2 and α7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity α4β2 ligand (Ki = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the α7 subtype (Ki = 6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (Ki = 50 nM for α4β2 and Ki = 1.6 μM for α7) evidenced a gain in the α4β2 versus α7 selectivity when compared with the model compound.

Graphical abstractAn efficient Stille coupling-based synthesis of epiboxidine and unsaturated analogues is reported. The compounds were assayed for their binding affinity at neuronal α4β2 and α7 nicotinic acetylcholine receptors.Figure optionsDownload full-size imageDownload as PowerPoint slide