title: Effects of ritobegron (KUC-7483), a novel selective β3-adrenoceptor agonist, on bladder function in cynomolgus monkey.
abstract: We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50) 8.2 ± 2.3 × 10(-7) M; maximal relaxation 88.7 ± 3.7%). The β(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 ± 1.2 × 10(-5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 ± 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective β(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.
authors.affiliation: Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano-Pref. 399-8304, Japan. itaru_maruyama@pharm.kissei.co.jp
authors.forename: Itaru
authors.initials: I
authors.lastname: Maruyama
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tatemichi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Goi
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Maruyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hoyano
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusama
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D014132:Trachea / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy; D010136:p-Hydroxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000085:Acetates; D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; C576375:ritobegron ethyl; D010136:p-Hydroxyamphetamine