Referenced in: none

Automatically associated channels: Kir2.3 , TRP , TRPV , TRPV1

Title: Effect of chirality and lipophilicity in the functional activity of evodiamine and its analogues at TRPV1 channels.

Authors: Luciano De Petrocellis, Aniello Schiano Moriello, Gabriele Fontana, Alessandro Sacchetti, Daniele Passarella, Giovanni Appendino, Vincenzo Di Marzo

Journal, date & volume: Br. J. Pharmacol., 2014 May , 171, 2608-20

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23902373

Abstract
Evodiamine, a racemic quinazolinocarboline alkaloid isolated from the traditional Chinese medicine Evodiae fructus, has been reported to act as an agonist of the transient receptor potential vanilloid type-1 (TRPV1) cation channel both in vitro and in vivo. Evodiamine is structurally different from all known TRPV1 activators, and has significant clinical potential as a thermogenic agent. Nevertheless, the molecular bases for its actions are still poorly understood.To investigate the structure-activity relationships of evodiamine, the natural racemate was resolved, and a series of 23 synthetic analogues was prepared, using as the end point the intracellular Ca(2+) elevation in HEK-293 cells stably overexpressing either the human or the rat recombinant TRPV1.S-(+) evodiamine was more efficacious and potent than R-(-) evodiamine, and a new potent lead (Evo30) was identified, more potent than the reference TRPV1 agonist, capsaicin. In general, potency and efficacy correlated with the lipophilicity of the analogues. Like other TRPV1 agonists, several synthetic analogues could efficiently desensitize TRPV1 to activation by capsaicin.Evodiamine qualifies as structurally unique lead structure to develop new potent TRPV1 agonists/desensitizers.