TRPM8 is activated by cold temperature and cooling compounds, menthol and icilin. TRPM8 is involved in cold allodynia and pain in urological and respiratory disorders. TRPM8 blocking drugs are being developed energetically as a new therapy for these disorders. Because only a few natural TRPM8 antagonists have been reported, the finding of new compounds having different structures from known antagonists could lead to develop new type of blockers.We are searching for TRP channel-effective substances from natural sources for TRP channel-target medicines. Here we found that voacangine from Voacanga africana having iboga structure is a novel strong TRPM8 antagonist.Mouse TRPM8-expressing HEK cells were used. Receptor responses were evaluated as increases of intracellular Ca2+ by using a microplate reader and a fluorescent microscope.Voacangine attenuated menthol- or icilin-induced TRPM8 activation in a concentration-dependent manner. Schild plot analysis showed that voacangine competitively inhibits menthol (pA2 = 5.07 � 0.12, KB =8.50 � 0.76 �M, slope = 1.1 � 0.0), but non-competitively antagonizes against icilin. The IC50 values of voacangine were 9 �M for menthol and 7 �M for icilin. Voacangine showed much stronger potency than capsazepine and any other natural ones, but a little weaker than BCTC against both menthol and icilin. Up to 30 �M, voacangine did not block cold-induced TRPM8 activation.Voacangine is the first natural competitive antagonist for TRPM8 with high potency and the first alkaloid antagonist for TRPM8. Since most of known TRPM8 antagonists are non-competitive, voacangine could contribute to develop new class of TRPM8 blocker.

New class TRPM8 antagonist, voacangine is the first natural competitive antagonist for menthol receptor, TRPM8

245th National Meeting (2013)

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