Effects of ritobegron (KUC-7483), a novel selective β3-adrenoceptor agonist, on bladder function in cynomolgus monkey

J Pharmacol Exp Ther. 2012 Jul;342(1):163-8. doi: 10.1124/jpet.112.191783. Epub 2012 Apr 16.

Abstract

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.

MeSH terms

  • 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
  • Trachea / drug effects
  • Urinary Bladder / drug effects*
  • Urinary Bladder / physiology
  • Urinary Bladder, Overactive / drug therapy
  • p-Hydroxyamphetamine / analogs & derivatives*
  • p-Hydroxyamphetamine / pharmacology

Substances

  • Acetates
  • Adrenergic beta-3 Receptor Agonists
  • Adrenergic beta-3 Receptor Antagonists
  • ritobegron ethyl
  • p-Hydroxyamphetamine