Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression

Jianhua Liu, Li Fang Yu, J. Brek Eaton, Barbara Caldarone, Katie Cavino, Christina Ruiz, Matthew Terry, Allison Fedolak, Daguang Wang, Afshin Ghavami, David A. Lowe, Dani Brunner, Ronald J. Lukas, Alan P. Kozikowski

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)7280-7288
Number of pages9
JournalJournal of medicinal chemistry
Volume54
Issue number20
DOIs
StatePublished - Oct 27 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Liu, J., Yu, L. F., Eaton, J. B., Caldarone, B., Cavino, K., Ruiz, C., Terry, M., Fedolak, A., Wang, D., Ghavami, A., Lowe, D. A., Brunner, D., Lukas, R. J., & Kozikowski, A. P. (2011). Discovery of isoxazole analogues of sazetidine-A as selective α4β2-nicotinic acetylcholine receptor partial agonists for the treatment of depression. Journal of medicinal chemistry, 54(20), 7280-7288. https://doi.org/10.1021/jm200855b