Activation of human and mouse transient receptor potential vanilloid 1 by enantiomeric evodiamine and rutaecarpine

Abstract

(+)-Evodiamine and rutaecarpine are the primary alkaloidal components of Euodia Fruit (EF; dried fruits of Euodia ruticarpa Bentham, Rutaceae) known to activate the transient receptor potential vanilloid 1 (TRPV1). Although evodiamine and rutaecarpine share similar chemical structures, their three-dimensional conformations differ due to the presence or absence of a carbon-nitrogen double bond in the five-membered ring. Furthermore, the enantiomer (−)-evodiamine does not naturally occur and exhibits a stereochemical configuration opposite to that of (+)-evodiamine. Therefore, elucidating the relationship between TRPV1 activity and these alkaloidal structures is essential. In this study, we evaluated the activation of human and mouse TRPV1 (hTRPV1 and mTRPV1, respectively) by (+)-evodiamine, (−)-evodiamine, (±)-evodiamine, and rutaecarpine using TRPV1-expressing cells. Evodiamine isolated from EF exhibited 89% enantiomeric excess (e.e.), and half-maximal effective concentrations (EC₅₀) of 0.34 and 0.031 µM for hTRPV1 and mTRPV1, respectively. Rutaecarpine activated mTRPV1 in a concentration-dependent manner up to 0.625 µM, but did not significantly activate hTRPV1. Furthermore, we synthesized high optical purity (+)-evodiamine and (−)-evodiamine and compared their effects on TRPV1 activation. The EC₅₀ value of (+)-evodiamine was 12 times lower than that of (−)-evodiamine for hTRPV1 activation; in contrast, the EC₅₀ of (+)-evodiamine was 7 times lower than that of (−)-evodiamine for mTRPV1 activation. These results suggest that the stereochemistry of Euodia alkaloids is crucial for TRPV1 activation.

Graphical abstract