PT  - JOURNAL ARTICLE
AU  - Fujimura, Morihiro
AU  - Izumimoto, Naoki
AU  - Momen, Shinobu
AU  - Yoshikawa, Satoru
AU  - Kobayashi, Ryosuke
AU  - Kanie, Sayoko
AU  - Hirakata, Mikito
AU  - Komagata, Toshikazu
AU  - Okanishi, Satoshi
AU  - Hashimoto, Tadatoshi
AU  - Yoshimura, Naoki
AU  - Kawai, Koji
TI  - Characteristics of TRK-130 (Naltalimide), a Novel Opioid Ligand, as a New Therapeutic Agent for Overactive Bladder
AID  - 10.1124/jpet.114.214031
DP  - 2014 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 543--551
VI  - 350
IP  - 3
4099  - http://jpet.aspetjournals.org/content/350/3/543.short
4100  - http://jpet.aspetjournals.org/content/350/3/543.full
SO  - J Pharmacol Exp Ther2014 Sep 01; 350
AB  - 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.