Discovery and Structure-Activity Relationship of Quinuclidine Benzamides as Agonists of alpha7 Nicotinic Acetylcholine Receptors

摘要

A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chi-meric receptor in a functional,cell-based,high-throughput assay.From this library,quinuclidine benzamides were found to have alpha7 nAChR agonist activity.The SAR diverged from the activity of this compound class verses the 5-HT_3 receptor,a structural homologue of the alpha7 nAChR.PNU-282987,the most potent compound from this series,was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.