| Effects of ritobegron (KUC-7483), a novel selective β3-adrenoceptor agonist, on bladder function in cynomolgus monkey. | |
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MedLine Citation:
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PMID: 22511202 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Itaru Maruyama; Satoshi Tatemichi; Yoshiaki Goi; Kazuyasu Maruyama; Yuji Hoyano; Yoshinobu Yamazaki; Hiroshi Kusama |
Publication Detail:
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Type: Journal Article Date: 2012-04-16 |
Journal Detail:
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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:
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Created Date: 2012-06-18 Completed Date: 2012-11-26 Revised Date: 2012-12-21 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 163-8 Citation Subset: IM |
Affiliation:
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Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano-Pref. 399-8304, Japan. itaru_maruyama@pharm.kissei.co.jp |
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetates
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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 Trachea / drug effects Urinary Bladder / drug effects*, physiology Urinary Bladder, Overactive / drug therapy p-Hydroxyamphetamine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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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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