Isolation, synthesis, and SAR study of voacangine-type alkaloids having thermosensitive TRP channels antagonistic activities

Abstract

Thermosensitive TRP channels such as TRPV1 and TRPM8 are implicated in pain. Voacangine is an iboga-type indole alkaloid in Voacanga africana, an apocynaceous plant which is used as traditional medicine in Africa. It was found that voacangine possessed antagonistic activities against TRPV1 or TRPM8 channels and was the first stimulus-selective TRPM8 antagonist. To investigate SAR, total syntheses of voacangine-related new alkaloids were done. A SAR study using voacangine and its related compounds on TRP channels antagonistic activities showed that catharanthine and dihydrocatharantine were potent TRPM8 antagonist and isoquinuclidine part having the same absolute configuration with voacangine was essential for chemical agonist-selective TRPM8 inhibition.