title: 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.
authors.affiliation: Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF , F-63000 Clermont-Ferrand, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vivier
authors.affiliation: Labex ICST, Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université Côte d'Azur , F-06560 Valbonne, France.
authors.forename: Ismail Ben
authors.initials: IB
authors.lastname: Soussia
authors.affiliation: Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF , F-63000 Clermont-Ferrand, France.
authors.forename: Nuno
authors.initials: N
authors.lastname: Rodrigues
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lolignier
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Maïly
authors.initials: M
authors.lastname: Devilliers
authors.affiliation: Labex ICST, Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université Côte d'Azur , F-06560 Valbonne, France.
authors.forename: Franck C
authors.initials: FC
authors.lastname: Chatelain
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Prival
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.affiliation: Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF , F-63000 Clermont-Ferrand, France.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bourdier
authors.affiliation: Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF , F-63000 Clermont-Ferrand, France.
authors.forename: Khalil
authors.initials: K
authors.lastname: Bennis
authors.affiliation: Labex ICST, Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université Côte d'Azur , F-06560 Valbonne, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lesage
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.|CHU Clermont-Ferrand , Service de Pharmacologie, F-63003 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
authors.affiliation: Université Clermont Auvergne, Inserm , Neuro-Dol, F-63000 Clermont-Ferrand, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.affiliation: Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF , F-63000 Clermont-Ferrand, France.
authors.forename: Sylvie
authors.identifier: 0000-0003-3347-4846
authors.initials: S
authors.lastname: Ducki
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D024683:Potassium Channels, Tandem Pore Domain / Q000819:agonists*
chemical_list: D000700:Analgesics; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1