Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with Î±4Î²2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the Î±4Î²2 subtype of nAChR over Î±3Î²4-nAChRs are partial agonists at the Î±4Î²2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline. Â© 2011 American Chemical Society.
Journal of Medicinal Chemistry
Digital Object Identifier (DOI)
Liu, Jianhua; Yu, Li Fang; Eaton, J. Brek; Caldarone, Barbara; Cavino, Katie; Ruiz, Christina; Terry, Matthew; Fedolak, Allison; Wang, Daguang; Ghavami, Afshin; Lowe, David A.; Brunner, Dani; Lukas, Ronald J.; and Kozikowski, Alan P., "Discovery Of Isoxazole Analogues Of Sazetidine-A As Selective Î±4Î²2-Nicotinic Acetylcholine Receptor Partial Agonists For The Treatment Of Depression" (2011). Neurobiology. 207.