AI Article Synopsis
- The alkaloid voacangine is identified as the first TRPM8 antagonist that selectively responds to specific stimuli.
- A study on natural indole alkaloid analogues demonstrated that dihydrocatharanthine and catharanthine effectively inhibit TRPM8, performing similarly to the known antagonist BCTC.
- The research highlights the importance of the iboga structure for TRPM8 inhibition, indicating that its specific stereochemistry is necessary for achieving selective antagonism.
Article Abstract
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.
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