Activation and Inhibition of Thermosensitive TRP Channels by Voacangine, an Alkaloid Present in Voacanga africana, an African. Tree

作者：Terada Yuko; Horie Syunji; Takayama Hiromitsu; Uchida Kunitoshi; Tominaga Makoto; Watanabe Tatsuo^*

来源：Journal of Natural Products, 2014, 77(2): 285-297.

DOI：10.1021/np400885u

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 mu M). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 mu M). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 mu M), but it showed noncompetitive inhibition against icilin (IC50, 7 mu M). 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.

• 出版日期2014-2