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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of (R)-2-(2-Aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} Acetanilide (YM178), a Novel Selective ₃-Adrenoceptor Agonist, on Bladder Function

Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan (T.T., M.U., S.S., Te.M., I.N., Ta.M., M.S., K.M.); and Department of Urology, Fukushima Medical University, Fukushima, Japan (H.U., O.M.)

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 ₃-adrenoceptor (AR). The half-maximal effective concentration (EC₅₀) value was 22.4 nM. EC₅₀ 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). EC₅₀ values of YM178 and isoproterenol in rat bladder strips precontracted with 10^–6 M CCh were 5.1 and 1.4 µM, respectively, whereas those in human bladder strips precontracted with 10^–7 M CCh were 0.78 and 0.28 µM, 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.

Address correspondence to: Dr. Toshiyuki Takasu, Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585 Japan. E-mail: toshiyuki.takasu{at}jp.astellas.com

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