Natural-Product-Derived Transient Receptor Potential Melastatin 8 (TRPM8) Channel Modulators

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• 作者：Christina M. LeGay ; Evgueni Gorobets ; Mircea Iftinca ; Rithwik Ramachandran ; Christophe Altier ; Darren J. Derksen
• 刊名：Organic Letters
• 出版年：2016
• 出版时间：June 3, 2016
• 年：2016
• 卷：18
• 期：11
• 页码：2746-2749
• 全文大小：330K
• 年卷期：0
• ISSN：1523-7052

文摘

A library of novel structural hybrids of menthol and cubebol was tested for each derivative’s ability to interact with the transient receptor potential subfamily melastatin member 8 (TRPM8) channel. This structure–activity relationship study revealed three potent modulators of the TRPM8 ion channel: a novel agonist (4) with an EC₅₀ value of 11 ± 1 μM, an antagonist (15) with an IC₅₀ value of 2 ± 1 μM, and an allosteric modulator (21) that minimized channel desensitization toward menthol. Each of these novel exocyclic olefin analogues of menthol is readily accessible by synthesis and was tested using Ca²⁺ assays and electrophysiology.