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.