(−)-Menthylamine derivatives as potent and selective antagonists of transient receptor potential melastatin type-8 (TRPM8) channels

A series of twenty-two (−)-menthylamine derivatives was synthesized and tested on TRPM8, TRPV1, and TRPA1 channels. Five of the novel compounds, that is, 1d, 1f, 2b, 2c, and 2e behaved as potent TRPM8 antagonists with IC50 values versus icilin and (−)-menthol between 20 nM and 0.7 μM, and were between 4- and ∼150-fold selective versus TRPV1 and TRPA1 activation. Compound 1d also induced caspase 3/7 release in TRPM8-expressing LNCaP prostate carcinoma cells, but not in non-TRPM8 expressing DU-145 cells. Five other derivatives, that is, 1a, 1g, 1h, 2f, and 2h were slightly less potent than previous compounds but still relatively selective versus TRPV1 and TRPA1.

The evaluation of a series of (−)-menthylamine derivatives led to the identification of some potent TRPM8 antagonists with IC50 values versus icilin and (−)-menthol between 20 nM and 0.7 μM and between 4- and ∼150-fold selective versus TRPV1 and TRPA1 activation.Figure optionsDownload as PowerPoint slide