Despite their discovery in the early 20th century and intensive study over the last 20 years, nicotinic acetylcholine receptors (nAChRs) are still far from being well understood. Only a few chemical entities targeting nAChRs are currently undergoing clinical trials, and even fewer have reached the marketplace. In our efforts to discover novel and truly selective nAChR ligands, we designed and synthesized a series of chiral cyclopropane-containing Î±4Î²2-specific ligands that display low nanomolar binding affinities and excellent subtype selectivity while acting as partial agonists at Î±4Î²2-nAChRs. Their favorable antidepressant-like properties were demonstrated in the classical mouse forced swim test. Preliminary ADMET studies and broad screening toward other common neurotransmitter receptors were also carried out to further evaluate their safety profile and eliminate their potential off-target activity. These highly potent cyclopropane ligands possess superior subtype selectivity compared to other Î±4Î²2-nAChR agonists reported to date, including the marketed drug varenicline, and therefore may fully satisfy the crucial prerequisite for avoiding adverse side effects. These novel chemical entities could potentially be advanced to the clinic as new drug candidates for treating depression. Â© 2011 American Chemical Society.
Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Zhang, Hankun; Tuckmantel, Werner; Eaton, J. Brek; Yuen, Po Wai; Yu, Li Fang; Bajjuri, Krishna Mohan; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Caldarone, Barbara; Paterson, Neil E.; Lowe, David A.; Brunner, Daniela; and Lukas, Ronald J., "Chemistry And Behavioral Studies Identify Chiral Cyclopropanes As Selective Î±4Î²2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting An Antidepressant Profile" (2012). Translational Neuroscience. 195.