Discovery and Structure−Activity Relationship of Quinuclidine Benzamides as Agonists of α7 Nicotinic Acetylcholine Receptors

A library of benzamides was tested for α7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have α7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT3 receptor, a structural homologue of the α7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native α7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.