2-(Arylmethyl)-3-substituted quinuclidines as selective α7 nicotinic receptor ligands

A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as α7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the α7 over other nAChRs (e.g., the α4β2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at α7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the α7 nAChR (EC50 = 33 nM, Imax = 1.0), at concentrations below those that result in desensitization.

Graphical abstractA series of 2-(arylmethyl)-3-substituted quinuclidines was developed as α7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model.Figure optionsDownload full-size imageDownload as PowerPoint slide