Effects of Ritobegron (KUC-7483), a Novel Selective β3-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey

• Published in: The Journal of pharmacology and experimental therapeutics 2012-07, Vol.342 (1), p.163-168
• Main Authors: Maruyama, Itaru, Tatemichi, Satoshi, Goi, Yoshiaki, Maruyama, Kazuyasu, Hoyano, Yuji, Yamazaki, Yoshinobu, Kusama, Hiroshi
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Adrenergic beta-3 Receptor Agonists - pharmacology; Adrenergic beta-3 Receptor Antagonists - pharmacology; Animals; Blood Pressure - drug effects; Female; Heart Atria - drug effects; Heart Rate - drug effects; Macaca fascicularis; Male; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; p-Hydroxyamphetamine - analogs & derivatives; p-Hydroxyamphetamine - pharmacology; Trachea - drug effects; Urinary Bladder - drug effects; Urinary Bladder - physiology; Urinary Bladder, Overactive - drug therapy
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.112.191783

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 (EC50 8.2 ± 2.3 × 10−7 M; maximal relaxation 88.7 ± 3.7%). The β3-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 (pKB value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC50 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 (ED50 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective β3-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.