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

BACKGROUND AND PURPOSE: Evodiamine, a racemic quinazolinocarboline alkaloid isolated from the traditional Chinese medicine Evodiae fructus, has been reported to acts 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 action are still poorly understood. EXPERIMENTAL APPROACH: To investigate the structure-activity relationships of evodiamine, the natural racemate was resolved, and a series of twenty-three synthetic analogues was prepared, using as the end-point the intracellular Ca2+ elevation in HEK-293 cells stably over-expressing either the human or the rat recombinant TRPV1. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: Evodiamine qualifies as structurally unique lead structure to develop new potent TRPV1 agonists/desensitizers.