Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan (O.N., Y.F., T.H., A.M., JI.K., H.H., Y.M., F.T.) and Department of Continence Medicine, the University of Tokyo Graduate School of Medicine, Tokyo, Japan (N.A., Y.I.)
Discovery Research R&D, Kissei Pharmaceutical Co., Ltd., Azumino, Japan (O.N., Y.F., T.H., A.M., JI.K., H.H., Y.M., F.T.) and Department of Continence Medicine, the University of Tokyo Graduate School of Medicine, Tokyo, Japan (N.A., Y.I.).
J Pharmacol Exp Ther. 2020 May;373(2):239-247. doi: 10.1124/jpet.119.263616. Epub 2020 Feb 26.
Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (A-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (-[()-3,3-difluoro-4-hydroxy-1-(2-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1-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.
瞬时受体电位（TRP）melastatin 8（TRPM8）是一种温度感应离子通道，主要表达于初级感觉神经元（背根神经节中的 A 纤维和 C 纤维）。在本报告中，我们对 KPR-5714（（（-3,3-二氟-4-羟基-1-（2-1,2,3-三唑-2-基）丁-2-基）-3-氟-2-[5-（4-氟苯基）-1-吡唑-3-基]苯甲酰胺）进行了表征，这是一种新型、选择性的 TRPM8 拮抗剂，用于评估其在过动性膀胱（OAB）大鼠模型中治疗频繁排尿的潜在疗效。在使用瞬时表达各种 TRP 通道的 HEK293T 细胞进行的钙内流测定中，KPR-5714 对 TRPM8 表现出强大的拮抗作用，并对其他 TRP 通道具有高选择性。静脉给予 KPR-5714 抑制了麻醉大鼠膀胱传入机械敏感 C 纤维的过度活跃，并剂量依赖性地增加了膀胱内注入乙酸缩短的收缩间期。此外，我们在大脑梗死和代谢笼实验中暴露于冷环境的清醒大鼠中检查了 KPR-5714 对排尿行为的影响。大脑梗死和寒冷暴露导致大鼠平均排尿量显著减少，排尿频率增加。口服给予 KPR-5714 剂量依赖性地增加了平均排尿量，降低了排尿频率，而对这些模型中的总排尿量没有影响。本研究表明，KPR-5714 通过抑制机械敏感膀胱 C 纤维的过度活跃改善了三种不同模型中的 OAB，并表明 KPR-5714 可能为 OAB 的治疗提供一种新的、有用的方法。 意义陈述：TRPM8 参与膀胱感觉转导，在超敏性膀胱疾病中异常激活。KPR-5714 作为一种新型、选择性的 TRPM8 拮抗剂，可能为与膀胱传入神经过度活跃相关的疾病提供一种有用的治疗方法，特别是在过动性膀胱中。
