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

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journal contribution
posted on 24.02.2005, 00:00 by Alice L. Bodnar, Luz A. Cortes-Burgos, Karen K. Cook, Dac M. Dinh, Vincent E. Groppi, Mihaly Hajos, Nicole R. Higdon, William E. Hoffmann, Raymond S. Hurst, Jason K. Myers, Bruce N. Rogers, Theron M. Wall, Mark L. Wolfe, Erik Wong
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.