This is the first report of TRPA1 activation by fatty acids. Activation of TRPA1 and TRPV1 induces thermogenesis and energy expenditure enhancement. In this study, we searched for novel agonists of TRPA1 and TRPV1 from a nonpungent food, royal jelly (RJ). We measured the activation of human TRPA1 and TRPV1 by RJ extracts and found that the hexane extract contains TRPA1 agonists. The main functional compounds in the hexane extract were trans-10-hydroxy-2-decenoic acid (HDEA) and 10-hydroxydecanoic acid (HDAA). These are characteristic fatty acids of RJ. Their EC50 values were about 1,000 times larger than that of AITC, and their maximal responses were equal. They activated TRPA1 more strongly than TRPV1. Their EC50 values for TRPV1 were 2 times larger, and the maximal response was less than half of that for TRPA1. Next, we studied the potencies of other lipid components for both receptors. Most of them have higher affinity to TRPA1 than TRPV1. Among them, dicarboxylic acids showed equal efficacy for both receptors, but those are present in only small amounts in RJ. We concluded that the main function of RJ is TRPA1 activation by HDEA and HDAA, the major components of the RJ lipid fraction.
The iboga alkaloid voacangine (1) has been reported previously to be the first stimulus-selective TRPM8 antagonist. In the present report, a structure-activity relationship (SAR) study is described on the effects of some naturally occurring indole alkaloid analogues on TRPM8 inhibition. Dihydrocatharanthine (10) and catharanthine (11) were found to be inhibitors of TRPM8 activity, and their IC50 values were equivalent to that of BCTC, a potent and representative TRPM8 antagonist. Furthermore, it was shown that the iboga moiety is the most crucial unit for TRPM8 blockade and that its stereostructure, as found in 1 but not in 10 and 11, is essential for chemical agonist-selective TRPM8 inhibition. These findings should provide useful information for synthesizing additional stimulus-selective and TRPM8-selective blockers.
Allyl isothiocyanate (ITC) (4) is the main pungent component in wasabi, and it generates an acrid sensation by activating TRPA1. The flavor and pungency of ITCs vary depending on the compound. However, the differences in activity to activate TRPA1 between ITCs are not known except for a few compounds. To investigate the effect of carbon chain length and substituents of ITCs, the TRPA1-activiting ability of 16 ITCs was measured. Since most of the ITCs showed nearly equal TRPA1-activiting potency, the ITC moiety is likely the predominant contributor to their TRPA1-activating abilities, and contributions of other functional groups to their activities to activate TRPA1 are comparatively small.
Voacangine (1) is an alkaloid found in the root bark of Voacanga africana. Our previous work has suggested that 1 is a novel transient receptor potential vanilloid type 1 (TRPV1) antagonist. In this study, the agonist and antagonist activities of 1 were examined against thermosensitive TRP channels. Channel activity was evaluated mainly using TRP channel-expressing HEK cells and calcium imaging. Herein, it was shown that 1 acts as an antagonist for TRPV1 and TRPM8 but as an agonist for TRPA1 (EC50, 8 μM). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 μM). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 μM), but it showed noncompetitive inhibition against icilin (IC50, 7 μM). Moreover, the compound selectively abrogated chemical agonist-induced TRPM8 activation and did not affect cold-induced activation. Among these effects, the TRPM8 inhibition profile is unique and noteworthy, because to date no studies have reported a menthol competitive inhibitor of TRPM8 derived from a natural source. Furthermore, this is the first report of a stimulus-selective TRPM8 antagonist. Accordingly, 1 may contribute to the development of a novel class of stimulus-selective TRPM8 blockers.
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