Development of the First Two-Pore Domain Potassium Channel TWIK-Related K+ Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity

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• 作者：Delphine Vivier ; Ismail Ben Soussia ; Nuno Rodrigues ; Stéphane Lolignier ; Maïly Devilliers ; Franck C. Chatelain ; Laetitia Prival ; Eric Chapuy ; Geoffrey Bourdier ; Khalil Bennis ; Florian Lesage ; Alain Eschalier ; Jérôme Busserolles ; Sylvie Ducki
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：1076-1088
• 全文大小：645K
• ISSN：1520-4804

文摘

The TWIK-related K⁺ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1–54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.