Document Detail

Effects of ritobegron (KUC-7483), a novel selective β3-adrenoceptor agonist, on bladder function in cynomolgus monkey.
MedLine Citation:
PMID:  22511202     Owner:  NLM     Status:  MEDLINE    
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.
Itaru Maruyama; Satoshi Tatemichi; Yoshiaki Goi; Kazuyasu Maruyama; Yuji Hoyano; Yoshinobu Yamazaki; Hiroshi Kusama
Publication Detail:
Type:  Journal Article     Date:  2012-04-16
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  342     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-18     Completed Date:  2012-11-26     Revised Date:  2012-12-21    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  163-8     Citation Subset:  IM    
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano-Pref. 399-8304, Japan.
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MeSH Terms
Acetates / pharmacology*
Adrenergic beta-3 Receptor Agonists / pharmacology*
Adrenergic beta-3 Receptor Antagonists / pharmacology
Blood Pressure / drug effects
Heart Atria / drug effects
Heart Rate / drug effects
Macaca fascicularis
Muscle Contraction / drug effects
Muscle Relaxation / drug effects
Trachea / drug effects
Urinary Bladder / drug effects*,  physiology
Urinary Bladder, Overactive / drug therapy
p-Hydroxyamphetamine / analogs & derivatives*,  pharmacology
Reg. No./Substance:
0/Acetates; 0/Adrenergic beta-3 Receptor Agonists; 0/Adrenergic beta-3 Receptor Antagonists; 0/ritobegron ethyl; 103-86-6/p-Hydroxyamphetamine

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