title: Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel.
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. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.
authors.affiliation: Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR6296, ICCF, F-63171 Aubière, France.
authors.forename: Nuno
authors.initials: N
authors.lastname: Rodrigues
authors.affiliation: CNRS, UMR6296, ICCF, F-63171 Aubière, France; Clermont Université, ENSCCF, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Khalil
authors.initials: K
authors.lastname: Bennis
authors.affiliation: Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France; CNRS, UMR6296, ICCF, F-63171 Aubière, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vivier
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, UMR1107, Neuro-Dol, F-63001 Clermont-Ferrand, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pereira
authors.affiliation: Labex ICST, Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université de Nice Sophia Antipolis, F-06560 Valbonne, France.
authors.forename: Franck
authors.initials: F
authors.lastname: C Chatelain
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, UMR1107, Neuro-Dol, F-63001 Clermont-Ferrand, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Chapuy
authors.affiliation: CNRS, UMR6296, ICCF, F-63171 Aubière, France; Clermont Université, ENSCCF, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Deokar
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, UMR1107, Neuro-Dol, F-63001 Clermont-Ferrand, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.affiliation: Labex ICST, Institut de Pharmacologie Moléculaire et Cellulaire, UMR CNRS 7275, Université de Nice Sophia Antipolis, F-06560 Valbonne, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Lesage
authors.affiliation: Clermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur, BP 10448, F-63000 Clermont-Ferrand, France; Inserm, UMR1107, Neuro-Dol, F-63001 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: CNRS, UMR6296, ICCF, F-63171 Aubière, France; Clermont Université, ENSCCF, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France. Electronic address: Sylvie.Ducki@ensccf.fr.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducki
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002109:Caffeic Acids / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004952:Esters / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy*; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000700:Analgesics; D002109:Caffeic Acids; D002934:Cinnamates; D004952:Esters; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1; C018253:alpha-cyanocinnamate; C040048:caffeic acid
keywords: Analgesic agents; Antinociceptive; Caffeate esters; Pain; QSAR; Structure–activity relationship study; TREK-1 channel