title: Effect of a Bicyclic Pyrimidine Derivative (KRP-103), a Novel Selective Tachykinin NK1 Receptor Antagonist, on Bladder Function in Guinea Pigs.
abstract: We evaluated the pharmacological characteristics of KRP-103, chemically named as ((2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluorometheyl)-phenylmethyl]-4- (2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one), and its effects on lower urinary tract function in guinea pigs. In radioligand binding assay, KRP-103 showed higher selectivity for human NK1 receptor (hNK1R) than for human NK2 receptor (hNK2R) and human NK3 receptor (hNK3R) (Ki for hNK1R, hNK2R and hNK3R=0.126 nM, > 10 000 nM and > 10 000 nM). In distention-induced rhythmic bladder contractions (RBCs) in urethane-anesthetized guinea pigs, intravenous administration of KRP-103 dose-dependently increased the shutdown time of RBCs and slightly decreased the amplitude of RBCs (only about 20%). In acutely spinalized guinea pig cystometory, intraduodenal administration of KRP-103 dose-dependently increased the effective bladder capacity with a minimum effective dose of 1 mg/kg. Furthermore, to clarify the site of action of KRP-103, we evaluated the inhibitory effects of KRP-103 on bladder contractions induced by electrical stimulation (ES) of the central or peripheral cut end of the pelvic nerve (PN). KRP-103 inhibited the bladder contractions induced by ES of the central cut end of PN but not those induced by ES of the peripheral cut end of PN. These results indicate that KRP-103 enhances bladder storage function by inhibiting sensory transmission from the bladder at the level of spinal cord without affecting bladder efferent function, suggesting that KRP-103 may be a suitable therapeutic drug for treatment of overactive bladder.
authors.affiliation: Department of Urology, Graduate School of Medicine, Gifu University, Gifu, Japan.|Watarase Research Center, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Asao
authors.initials: A
authors.lastname: Tanioka
authors.affiliation: Department of Urology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Deguchi
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology*; D010079:Oxazocines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D015320:Tachykinins / Q000378:metabolism*; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy / Q000378:metabolism
chemical_list: C527215:KRP-103; D064729:Neurokinin-1 Receptor Antagonists; D010079:Oxazocines; D011743:Pyrimidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C030986:pyrimidine