title: Characterisation of TRPM8 as a pharmacophore receptor.
abstract: Some proteins of the transient receptor potential (TRP) family form temperature sensitive ion channels. One member of the melastatin (M) group, namely TRPM8 is activated by cold and cooling compounds such as menthol and icilin, and its gene is up-regulated in prostate cancer and other malignancies. Here we characterise the effects of the carboxamides WS-12, CPS-113, CPS-369, the carboxylic acid WS-30 and the phosphine oxide WS-148 by Ca2+ imaging experiments and whole-cell patch-clamp recordings on TRPM8 expressing human embryonic kidney (HEK), lymph node prostate cancer (LNCaP) and dorsal root ganglia (DRG) cells. The cooling compounds introduced in this study, show a dose-dependent and reversible activation of TRPM8 with EC50 values in the nM to low microM range. The carboxamide WS-12 is most potent in activating TRPM8. It is selective, since other TRP proteins are not stimulated at muM concentrations and its efficacy with respect to TRPM8 is similar to the one of icilin. In summary, the compounds described in this study represent new tools to dissect TRPM8 functions and may serve as chemical leads for the development of additional TRPM8 agonists and novel antagonists. Such compounds may be beneficial for preventing noxious cold perception. They could also be useful in diagnosis and treatment of most common cancers in which the TRPM8 gene is up-regulated in comparison to the corresponding normal tissue.
authors.affiliation: Experimentelle und Klinische Pharmakologie und Toxikologie, Universität des Saarlandes, D-66421 Homburg, Germany. matthias.boedding@uniklinik-saarland.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Bödding
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wissenbach
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D003592:Cytophotometry; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008610:Menthol / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010720:Phosphines / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D002264:Carboxylic Acids; D010087:Oxides; D010720:Phosphines; D011744:Pyrimidinones; D018160:Receptors, Cytoplasmic and Nuclear; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D008610:Menthol; C490483:icilin