Evodiamine functions as an agonist for the vanilloid receptor TRPV1

Abstract

Evodiamine, a quinozole alkaloid constituent of Evodia rutaecarpa, has been reported previously to induce several responses comparable to capsaicin in animal systems. Here, we characterize evodiamine as an agonist for rat TRPV1 expressed heterologously in CHO cells. Evodiamine bound to rat TRPV1 with a Ki of 5.95 +/- 0.87 microM, as measured by inhibition of [3H] RTX binding (capsaicin, Ki = 1.8 +/- 0.3 microM). Evodiamine was a full agonist for induction of 45Ca2+ uptake, with an EC50 of 856 +/- 43 nM (capsaicin, EC50 = 45 +/- 4 nM) and was competitively antagonized by capsazepine, as revealed by a Schild plot. The pattern of cellular response, as determined by calcium imaging, was similar to that with capsaicin and yielded an EC(50) of 1.03 +/- 0.21 [micro sign]M. Molecular modeling suggested a consistent pattern of overlap between evodiamine and TRPV1 agonists. We conclude that evodiamine represents a novel class of agonists for rat TRPV1, albeit 3-19-fold less potent than capsaicin, and thus represents a new potential class of lead molecules for drug development.

Anti-inflammatory and anti-infectious effects of Evodia rutaecarpa (Wuzhuyu) and its major bioactive components

“…A study found that Evo was an agonist for the vanilloid receptor TRPV1 in rat, about 3-19 fold less potent than capsaicin [32]. Moreover, Evo was found to protect bovine serum albumin induced guinea-pig cardiac anaphylaxis by stimulation of CGRP release [33] and exert protection against myocardial ischemia-reperfusion injury in rats by activation of vanilloid receptors to stimulate the CGRP release [34].…”

Implication of AMP-Activated Protein Kinase in Transient Receptor Potential Vanilloid Type 1-Mediated Activation of Endothelial Nitric Oxide Synthase

“…The transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated cationic channel, is a molecular integrator of multiple chemical and physical stimuli such as evodiamine (an active ingredient of evodia fruit), capsaicin (an active ingredient of hot pepper), anandamide, heat and protons (1)(2)(3)(4)(5). Activation of TRPV1 in neurons increases calcium (Ca 2+ ) entry, which elevates the intracellular Ca 2+ level, thus leading to the excitation of sensory neurons (2).…”

The Role of Natural Products in the Ligand Deorphanization of TRP Channels

“…The vanilloid activity of EVO has also been confirmed in cellular assays, where it behaves as a full agonist at rTRPV1, 3-fold less potent than capsaicin in binding assays, and 19-fold less potent for calcium uptake [47]. EVO does not apparently show any structural resemblance with capsaicin, but molecular modeling evidenced that the classic elements of the capsaicinoid pharmacophore (two lipophilic moieties separated by a H-bonding donor/acceptor moiety) can be recognized in its structure, with the indole nitrogen acting as a Hbonding donor and the quinazolone carbonyl as a H-bonding acceptor [47]. On the other hand, EVO can be also viewed as a conformationally constrained tryptamin derivative, and bear therefore a certain resemblance with the endogenous vanilloid antagonist Narachidonoylserotonin (AA-5-HT, 11) [38].…”

“…The vanilloid profile of EVO includes contraction of guinea pig bronchus, cardiotonic effects on isolated guinea pig atria, irritation in the mouse paw licking assay, and inhibition of acetic acid-induced writhing in the mouse [46]. The vanilloid activity of EVO has also been confirmed in cellular assays, where it behaves as a full agonist at rTRPV1, 3-fold less potent than capsaicin in binding assays, and 19-fold less potent for calcium uptake [47]. EVO does not apparently show any structural resemblance with capsaicin, but molecular modeling evidenced that the classic elements of the capsaicinoid pharmacophore (two lipophilic moieties separated by a H-bonding donor/acceptor moiety) can be recognized in its structure, with the indole nitrogen acting as a Hbonding donor and the quinazolone carbonyl as a H-bonding acceptor [47].…”