Discovery of Highly Potent and Selective 伪4尾2-Nicotinic Acetylcholine Receptor (nAChR) Partial Agonists Containing an Isoxazolylpyridine Ether Scaffold that Demonstrate Antidepressant-like Activity. P

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• 作者：Li-Fang Yu ; J. Brek Eaton ; Allison Fedolak ; Han-Kun Zhang ; Taleen Hanania ; Dani Brunner ; Ronald J. Lukas ; Alan P. Kozikowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9998-10009
• 全文大小：412K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

In our continued efforts to develop 伪4尾2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure鈥揳ctivity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [³H]epibatidine binding studies together with functional assays based on ⁸⁶Rb⁺ ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics.