Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels

M. Azhar Sherkheli, Guenter Gisselmann, Julia Franca Doerner, Hanns Hatt
Ruhr-University Bochum, Bochum/ NRW, Germany

Transient receptor potential melastatin-8 (TRPM8), a cationic ion channel is involved in detection of normal cooling-sensation in humans and rodents. Previous studies show that TRPM8 activation by cooling or chemical agonists produces profound, mechanistically novel analgesia in chronic pain states such as neuropathic pain in rodents. Known TRPM8 agonists such as menthol and icilin have a relatively low potency and cross-activate nociceptors like TRPA1; thus bearing a limited therapeutic usefulness. For that reason, characterising ligands, which selectively activate TRPM8, presents a clinical and experimental need that requires urgent attention. Using Xenopus laevis oocytes as expression system, we evaluated WS-12, a menthol derivative, for its potential interaction with all thermo-sensitive TRP ion channels. Oocytes were superfused with the test and standard substances respectively. Evoked responses were measured by two-electrode voltage clamp technique and the magnitudes of currents were compared with baseline values. WS-12 robustly activated TRPM8 in low micromolar concentrations (EC50 12±5 μM) thereby displaying a higher potency and efficacy compared to menthol (EC50 196±22 μM). Any of the other described thermo-sensitive TRP ion channels including TRPV1, TRPV2, TRPV3, TRPV4 and TRPA1 were not activated at a concentration (1 mM) saturating for TRPM8 responses; a characteristic which is in sharp contrast to menthol as it activates TRPA1 and TRPV3 in addition to TRPM8. Unlike icilin, WS-12 does not desensitise TRPM8 channels to repeated exposure of 1 mM saturating doses. In addition, acidosis or variations in extracellular calcium have no influence on potency/efficacy of WS-12 for TRPM8. The selectivity profile of WS-12, its several-fold higher potency and around two-fold increase in efficacy compared to menthol warrants its potential utility for therapy in chronic neuropathic pain states and as a diagnostic probe in prostate cancer.