title: Characteristics of TRK-130 (Naltalimide), a novel opioid ligand, as a new therapeutic agent for overactive bladder.
abstract: We characterized TRK-130 (N-[(5R,6R,14S)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]phthalimide; naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand-binding assays with cells expressing human µ-opioid receptors (MORs), δ-opioid receptors (DORs), or κ-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (Ki for MORs, DORs, and KORs = 0.268, 121, and 8.97 nM, respectively). In a functional assay (cAMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC50 (Emax) for MORs, DORs, and KORs = 2.39 nM (66.1%), 26.1 nM (71.0%), and 9.51 nM (62.6%), respectively]. In isovolumetric rhythmic bladder contractions (RBCs) in anesthetized guinea pigs, TRK-130 dose-dependently prolonged the shutdown time (the duration of complete cessation of the bladder contractions) (ED30 = 0.0034 mg/kg i.v.) without affecting amplitude of RBCs. Furthermore, TRK-130 ameliorated formalin-induced frequent urination at doses of higher than 0.01 mg/kg p.o. in guinea pigs under the freely moving condition. Meanwhile, TRK-130 showed only a negligible effect on the gastrointestinal transit at doses of up to 10 mg/kg s.c. in mice. These results indicate that TRK-130 is a potent and selective human MOR partial agonist without undesirable opioid adverse effects such as constipation and enhances the storage function by suppressing the afferent limb of the micturition reflex pathway, suggesting that TRK-130 would be a new therapeutic agent for OAB.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.) Morihiro_Fujimura@nts.toray.co.jp.
authors.forename: Morihiro
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Izumimoto
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Shinobu
authors.initials: S
authors.lastname: Momen
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Satoru
authors.initials: S
authors.lastname: Yoshikawa
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Sayoko
authors.initials: S
authors.lastname: Kanie
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Mikito
authors.initials: M
authors.lastname: Hirakata
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Komagata
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okanishi
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., Kanagawa, Japan (M.F., N.I., S.M., S.Y., R.K., S.K., M.H., T.K., K.K.); Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa, Japan (S.O., T.H.); and Departments of Urology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania (N.Y.).
authors.forename: Koji
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D009019:Morphinans / Q000737:chemistry / Q000627:therapeutic use*; D010797:Phthalimides / Q000737:chemistry / Q000627:therapeutic use*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D009019:Morphinans; C000591921:N-(17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl)phthalimide; D010797:Phthalimides