Development of the first two-pore domain potassium channel TWIK-related K+ channel 1-selective agonist possessing in Vivo antinociceptive activity.

Abstract : 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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https://hal.archives-ouvertes.fr/hal-01540830
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Submitted on : Friday, June 16, 2017 - 4:06:40 PM
Last modification on : Friday, September 14, 2018 - 1:12:42 AM

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Delphine Vivier, Ismail Ben Soussia, Nuno Rodrigues, Stéphane Lolignier, Maïly Devilliers, et al.. Development of the first two-pore domain potassium channel TWIK-related K+ channel 1-selective agonist possessing in Vivo antinociceptive activity.. Journal of Medicinal Chemistry, American Chemical Society, 2017, 60, pp.1076-1088. ⟨10.1021/acs.jmedchem.6b01285⟩. ⟨hal-01540830⟩

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