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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Vivier, Delphine | Soussia, Ismail Ben | Rodrigues, Nuno | Lolignier, Stéphane | Devilliers, Maïly | Chatelain, Franck, Claude | Prival, Laetitia | Chapuy, Eric | Bourdier, Geoffrey | Bennis, Khalil | Lesage, Florian | Eschalier, Alain | Busserolles, Jérôme | Ducki, Sylvie

Edité par CCSD ; American Chemical Society -

International audience. 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.

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