Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective 伪4尾2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II

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• 作者：Han-Kun Zhang ; Li-Fang Yu ; J. Brek Eaton ; Paul Whiteaker ; Oluseye K. Onajole ; Taleen Hanania ; Daniela Brunner ; Ronald J. Lukas ; Alan P. Kozikowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5495-5504
• 全文大小：370K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at 伪4尾2-nicotinic acetylcholine receptors. In this study, a systematic structure鈥揳ctivity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.