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

We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta(3)-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta(1)- and beta(2)-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta(3)-ARs, 0.1 for human beta(1)-ARs, and 0.1 for human beta(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) (beta(3)-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 mu M, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 mu 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.