Department
neurobiology
Document Type
Article
Abstract
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 α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 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. © 2011 American Chemical Society.
Publication Date
10-27-2011
Publication Title
Journal of Medicinal Chemistry
ISSN
00222623
Volume
54
Issue
20
First Page
7280
Last Page
7288
Digital Object Identifier (DOI)
10.1021/jm200855b
Recommended Citation
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 α4β2-Nicotinic Acetylcholine Receptor Partial Agonists For The Treatment Of Depression" (2011). Translational Neuroscience. 207.
https://scholar.barrowneuro.org/neurobiology/207