Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel

Eur J Med Chem. 2014 Mar 21:75:391-402. doi: 10.1016/j.ejmech.2014.01.049. Epub 2014 Jan 31.

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.

Keywords: Analgesic agents; Antinociceptive; Caffeate esters; Pain; QSAR; Structure–activity relationship study; TREK-1 channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / chemistry*
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Caffeic Acids / chemistry*
  • Caffeic Acids / pharmacology
  • Caffeic Acids / therapeutic use*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology
  • Cinnamates / therapeutic use
  • Esters / chemistry
  • Esters / pharmacology
  • Esters / therapeutic use
  • Male
  • Mice
  • Models, Molecular
  • Pain / drug therapy*
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Quantitative Structure-Activity Relationship
  • Xenopus

Substances

  • Analgesics
  • Caffeic Acids
  • Cinnamates
  • Esters
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1
  • alpha-cyanocinnamate
  • caffeic acid