TY - JOUR T1 - Effects of Ritobegron (KUC-7483), a Novel Selective β<sub>3</sub>-Adrenoceptor Agonist, on Bladder Function in Cynomolgus Monkey JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 163 LP - 168 DO - 10.1124/jpet.112.191783 VL - 342 IS - 1 AU - Itaru Maruyama AU - Satoshi Tatemichi AU - Yoshiaki Goi AU - Kazuyasu Maruyama AU - Yuji Hoyano AU - Yoshinobu Yamazaki AU - Hiroshi Kusama Y1 - 2012/07/01 UR - http://jpet.aspetjournals.org/content/342/1/163.abstract N2 - 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. ER -