Effect of (R)-2-(2-Aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective β₃-Adrenoceptor Agonist, on Bladder Function

Abstract

We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4Ј-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human ␤ 3 -adrenoceptor (AR). The half-maximal effective concentration (EC 50 ) value was 22.4 nM. EC 50 values of YM178 for human ␤ 1 -and ␤ 2 -ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective ␤-AR agonist) was 0.8 for human ␤ 3 -ARs, 0.1 for human ␤ 1 -ARs, and 0.1 for human ␤ 2 -ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (␤ 3 -AR agonist). EC 50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10 Ϫ6 M CCh were 5.1 and 1.4 M, respectively, whereas those in human bladder strips precontracted with 10 Ϫ7 M CCh were 0.78 and 0.28 M, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

“…In human embryonic kidney (HEK) cells stably transfected with human β 3 -adrenoceptors at a density of 121-fmol/mg protein, mirabegron and isoprenaline exhibited apparent affinities of 55 nM and 34 μM, respectively, in competition radioligand binding studies, and these affinities were not substantially altered in HEK cells transfected with several naturally occurring gene variants of the receptor ). In cyclic AMP accumulation experiments in these HEK cells, mirabegron and isoprenaline exhibited EC 50 values of 0.93 and 11.2 nM, respectively, and the efficacy of mirabegron relative to isoprenaline was 0.85, which is in good agreement with the findings in CHO cells (Hatanaka et al 2013b;Takasu et al 2007). The potency and efficacy of mirabegron also was not affected by genotype in these experiments.…”

“…Two studies on CHO cells transfected with human β-adrenoceptor subtypes were reported with rather similar results. Thus, mirabegron stimulated cyclic AMP accumulation via β 3 -adrenoceptors with EC 50 values of 22 nM (Takasu et al 2007) and 1.5 nM (Hatanaka et al 2013b), its efficacy relative to isoprenaline was 0.8 in both studies; in contrast, efficacy at human β 1 -and β 2 -adrenoceptors was only 0.1-0.2 in both studies, which did not allow quantification of potency. In human embryonic kidney (HEK) cells stably transfected with human β 3 -adrenoceptors at a density of 121-fmol/mg protein, mirabegron and isoprenaline exhibited apparent affinities of 55 nM and 34 μM, respectively, in competition radioligand binding studies, and these affinities were not substantially altered in HEK cells transfected with several naturally occurring gene variants of the receptor ).…”

“…Similar to isoprenaline, mirabegron was somewhat more potent in human than in rat isolated bladder but, in both tissues, had an efficacy which was at least as large as that of isoprenaline (Takasu et al 2007). In another study in rat bladder, a comparable potency of mirabegron was detected, but, in that study, the efficacy relative to isoprenaline was slightly smaller .…”

“…In the urethane-anesthetized rat, i.v. administration of mirabegron produced a dose-dependent reduction in the frequency of rhythmic bladder contractions but did not significantly decrease contraction amplitude in doses up to 3 mg/kg; in contrast, the muscarinic antagonist oxybutynin increased contraction frequency and reduced contraction amplitude (Takasu et al 2007). In pentobarbital-anesthetized rats, i.v.…”

Detrusor myocyte activity and afferent signaling

“…b 3 -AR selective agonists are currently being evaluated as potential treatment for OAB in humans. 125 One of these, YM187, which mediated muscle relaxation in human bladder strips, 126 was given to patients with OAB in a controlled clinical trial. 127 The primary efficacy analysis showed a statistically significant reduction in mean micturition frequency Neurourology and Urodynamics DOI 10.1002/nau compared to placebo.…”