title: Bladder selectivity of the novel β₃-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat.
abstract: We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. β(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human β-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human β-AR, its selectivity for β(3)-AR being 301-fold and 32-fold higher versus β(1)-AR and β(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the β(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective β(3)-AR agonistic activity toward transfected human β-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. itaru_maruyama@pharm.kissei.co.jp
authors.forename: Itaru
authors.initials: I
authors.lastname: Maruyama
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Goi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tatemichi
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; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D001743:Urinary Bladder / Q000187:drug effects*; 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; D000318:Adrenergic beta-Agonists; D005576:Colforsin; D000242:Cyclic AMP; C576375:ritobegron ethyl; D010136:p-Hydroxyamphetamine; D007545:Isoproterenol