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
Externally publishedYes

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Isoxazoles
Cholinergic Agonists
Nicotinic Receptors
Ether
Antidepressive Agents
Neurotransmitter Receptor
Ligands
Neurotransmitter Transport Proteins
Mecamylamine
Serotonin Uptake Inhibitors
Cholinergic Antagonists
Structure-Activity Relationship
Depression
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity. / Yu, Li Fang; Tückmantel, Werner; Eaton, J. Brek; Caldarone, Barbara; Fedolak, Allison; Hanania, Taleen; Brunner, Dani; Lukas, Ronald J.; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 55, No. 2, 26.01.2012, p. 812-823.

Research output: Contribution to journalArticle

Yu, LF, Tückmantel, W, Eaton, JB, Caldarone, B, Fedolak, A, Hanania, T, Brunner, D, Lukas, RJ & Kozikowski, AP 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, vol. 55, no. 2, pp. 812-823. https://doi.org/10.1021/jm201301h
Yu, Li Fang ; Tückmantel, Werner ; Eaton, J. Brek ; Caldarone, Barbara ; Fedolak, Allison ; Hanania, Taleen ; Brunner, Dani ; Lukas, Ronald J. ; Kozikowski, Alan P. / Identification of novel α4β2-nicotinic acetylcholine receptor (nAChR) agonists based on an isoxazole ether scaffold that demonstrate antidepressant-like activity. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 2. pp. 812-823.
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