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 alpha 4 beta 2 and alpha 7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity alpha 4 beta 2 ligand (K-i = 0.4 nM) and, interestingly, evidenced a relevant affinity also for the alpha 7 subtype (K-i = 6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K-i = 50 nM for alpha 4 beta 2 and K-i = 1.6 mu M for alpha 7) evidenced a gain in the alpha 4 beta 2 versus 00 selectivity when compared with the model compound.