@article {Nakanishijpet.119.263616, author = {Osamu Nakanishi and Yoshikazu Fujimori and Naoki Aizawa and Takemitsu Hayashi and Akane Matsuzawa and Jun-Ichi Kobayashi and Hideaki Hirasawa and Yosuke Mutai and Fumiya Tanada and Yasuhiko Igawa}, title = {KPR-5714, a Novel Transient Receptor Potential Melastatin 8 (TRPM8) Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats}, elocation-id = {jpet.119.263616}, year = {2020}, doi = {10.1124/jpet.119.263616}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers, and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB.SIGNIFICANCE STATEMENT TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2020/02/26/jpet.119.263616}, eprint = {https://jpet.aspetjournals.org/content/early/2020/02/26/jpet.119.263616.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }