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Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels.
Pak J Pharm Sci. 2008 Oct; 21(4):370-8.PJ

Abstract

Transient receptor potential melastatin-8 (TRPM8), a cationic ion channel is involved in detection of normal cooling-sensation in mammals. TRPM8 activation by cooling or chemical agonists have been shown to produce 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 need. Using Xenopus laevis oocytes as expression system, we evaluated WS-12, a menthol derivative, for its potential interaction with all six thermo-sensitive TRP ion channels. Oocytes were injected with cRNA of gene of interest and incubated for 3-5 days (at 16 degrees C) before testing for functional characterisation of the recombinant ion channels. Oocytes were superfused with the test and standard substances respectively. Responses were measured by two-electrode voltage clamp technique and the amplitudes of evoked currents were compared with baseline values. WS-12 robustly activated TRPM8 in low micromolar concentrations (EC50 12+/-5 microM) thereby displaying a higher potency and efficacy compared to menthol (EC50 196+/-22 microM). Any of the other described thermo-sensitive TRP ion channel including TRPV1, TRPV2, TRPV3, TRPV4 and TRPA1 were not activated at a concentration (1 mM) optimally effective for TRPM8 responses; a characteristic which is in sharp contrast to menthol as it activates TRPA1 and TRPV3 in addition to TRPM8. Unlike icilin (75% reduction; p<0.001, n=6), WS-12 does not induce tachyphylaxis (4+/-2.3% increase in responses; p<0.08, n=6) of TRPM8 mediated currents to repeated exposure of 1 mM 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.

Authors+Show Affiliations

Department of Cell Physiology, Faculty of Biology & Biotechnology, Ruhr-University-Bochum, University Street 150, Bochum 44801, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18930858

Citation

Ma, Sherkheli, et al. "Menthol Derivative WS-12 Selectively Activates Transient Receptor Potential Melastatin-8 (TRPM8) Ion Channels." Pakistan Journal of Pharmaceutical Sciences, vol. 21, no. 4, 2008, pp. 370-8.
Ma S, G G, Ak VE, et al. Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci. 2008;21(4):370-8.
Ma, S., G, G., Ak, V. E., Jf, D., & H, H. (2008). Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pakistan Journal of Pharmaceutical Sciences, 21(4), 370-8.
Ma S, et al. Menthol Derivative WS-12 Selectively Activates Transient Receptor Potential Melastatin-8 (TRPM8) Ion Channels. Pak J Pharm Sci. 2008;21(4):370-8. PubMed PMID: 18930858.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. AU - Ma,Sherkheli, AU - G,Gisselmann, AU - Ak,Vogt-Eisele, AU - Jf,Doerner, AU - H,Hatt, PY - 2008/10/22/pubmed PY - 2008/12/23/medline PY - 2008/10/22/entrez SP - 370 EP - 8 JF - Pakistan journal of pharmaceutical sciences JO - Pak J Pharm Sci VL - 21 IS - 4 N2 - Transient receptor potential melastatin-8 (TRPM8), a cationic ion channel is involved in detection of normal cooling-sensation in mammals. TRPM8 activation by cooling or chemical agonists have been shown to produce 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 need. Using Xenopus laevis oocytes as expression system, we evaluated WS-12, a menthol derivative, for its potential interaction with all six thermo-sensitive TRP ion channels. Oocytes were injected with cRNA of gene of interest and incubated for 3-5 days (at 16 degrees C) before testing for functional characterisation of the recombinant ion channels. Oocytes were superfused with the test and standard substances respectively. Responses were measured by two-electrode voltage clamp technique and the amplitudes of evoked currents were compared with baseline values. WS-12 robustly activated TRPM8 in low micromolar concentrations (EC50 12+/-5 microM) thereby displaying a higher potency and efficacy compared to menthol (EC50 196+/-22 microM). Any of the other described thermo-sensitive TRP ion channel including TRPV1, TRPV2, TRPV3, TRPV4 and TRPA1 were not activated at a concentration (1 mM) optimally effective for TRPM8 responses; a characteristic which is in sharp contrast to menthol as it activates TRPA1 and TRPV3 in addition to TRPM8. Unlike icilin (75% reduction; p<0.001, n=6), WS-12 does not induce tachyphylaxis (4+/-2.3% increase in responses; p<0.08, n=6) of TRPM8 mediated currents to repeated exposure of 1 mM 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. SN - 1011-601X UR - https://www.unboundmedicine.com/medline/citation/18930858/Menthol_derivative_WS_12_selectively_activates_transient_receptor_potential_melastatin_8__TRPM8__ion_channels_ L2 - https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=500 DB - PRIME DP - Unbound Medicine ER -