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

被引:266
作者
Takasu, Toshiyuki
Ukai, Masashi
Sato, Shuichi
Matsui, Tetsuo
Nagase, Itsuro
Maruyama, Tatsuya
Sasamata, Masao
Miyata, Keiji
Uchida, Hisashi
Yamaguchi, Osamu
机构
[1] Astellas Pharma Inc, Inst Drug Discovery Res, Pharmacol Res Labs, Tsukuba, Ibaraki 3058585, Japan
[2] Fukushima Med Univ, Dept Urol, Fukushima, Japan
关键词
D O I
10.1124/jpet.106.115840
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:642 / 647
页数:6
相关论文
共 28 条
[1]   ATYPICAL BETA-ADRENOCEPTOR ON BROWN ADIPOCYTES AS TARGET FOR ANTI-OBESITY DRUGS [J].
ARCH, JRS ;
AINSWORTH, AT ;
CAWTHORNE, MA ;
PIERCY, V ;
SENNITT, MV ;
THODY, VE ;
WILSON, C ;
WILSON, S .
NATURE, 1984, 309 (5964) :163-165
[2]   DISTRIBUTION OF BETA(3)-ADRENOCEPTOR MESSENGER-RNA IN HUMAN TISSUES [J].
BERKOWITZ, DE ;
NARDONE, NA ;
SMILEY, RM ;
PRICE, DT ;
KREUTTER, DK ;
FREMEAU, RT ;
SCHWINN, DA .
EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION, 1995, 289 (02) :223-228
[3]   Functional pharmacological characterization of the muscarinic cholinoceptor-mediated inhibition of adenylyl cyclase in primary cultured human bladder detrusor smooth muscle cells. [J].
Daniels, DV ;
Meloy, TD ;
Loury, DN ;
Watson, N ;
Hegde, SS ;
Ford, APDW ;
Eglen, RM .
LIFE SCIENCES, 1999, 64 (6-7) :590-590
[4]  
DOLAN JA, 1994, J PHARMACOL EXP THER, V269, P1000
[5]   MOLECULAR CHARACTERIZATION OF THE HUMAN BETA-3-ADRENERGIC RECEPTOR [J].
EMORINE, LJ ;
MARULLO, S ;
BRIENDSUTREN, MM ;
PATEY, G ;
TATE, K ;
DELAVIERKLUTCHKO, C ;
STROSBERG, AD .
SCIENCE, 1989, 245 (4922) :1118-1121
[6]   Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol? [J].
Frazier, EP ;
Mathy, MJ ;
Peters, SLM ;
Michel, MC .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 313 (01) :260-267
[7]   Expression and possible functional role of the β3-adrenoceptor in human and rat detrusor muscle [J].
Fujimura, T ;
Tamura, K ;
Tsutsumi, T ;
Yamamoto, T ;
Nakamura, K ;
Koibuchi, Y ;
Kobayashi, M ;
Yamaguchi, O .
JOURNAL OF UROLOGY, 1999, 161 (02) :680-685
[8]  
Furuno T, 2006, NEUROUROL URODYNAM, V25, P590
[9]  
GRANNEMAN JG, 1991, MOL PHARMACOL, V40, P895
[10]   Functional role of M-2 and M-3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo [J].
Hegde, SS ;
Choppin, A ;
Bonhaus, D ;
Briaud, S ;
Loeb, M ;
Moy, TM ;
Loury, D ;
Eglen, RM .
BRITISH JOURNAL OF PHARMACOLOGY, 1997, 120 (08) :1409-1418