期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 75, 期 -, 页码 391-402出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.01.049
关键词
TREK-1 channel; Pain; Antinociceptive; Caffeate esters; Structure-activity relationship study; QSAR; Analgesic agents
资金
- Regional Council of Auvergne (Conseil Regional d'Auvergne)
- European Fund for Regional Economic Development (FEDER)
- Novartis Training Scheme
- French Ministry of Higher Education and Research (MESR)
- French National Research Agency (ANR) [ANR-12-EMMA-0017-01]
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-alpha-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. (C) 2014 Elsevier Masson SAS. All rights reserved.
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