Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity

Li Fang Yu, Werner Tückmantel, J. Brek Eaton, Barbara Caldarone, Allison Fedolak, Taleen Hanania, Dani Brunner, Ronald J. Lukas, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening toward other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.

Original languageEnglish (US)
Pages (from-to)812-823
Number of pages12
JournalJournal of medicinal chemistry
Volume55
Issue number2
DOIs
StatePublished - Jan 26 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Yu, L. F., Tückmantel, W., Eaton, J. B., Caldarone, B., Fedolak, A., Hanania, T., Brunner, D., Lukas, R. J., & Kozikowski, A. P. (2012). Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity. Journal of medicinal chemistry, 55(2), 812-823. https://doi.org/10.1021/jm201301h