Fukuta Y, Fukuda Y, Higashino R, Yoshida K, Ogishima M, Tamaki H, Takei M
Central Research Laboratories, Zeria Pharmaceutical Co. Ltd., Saitama, Japan.
J Pharmacol Exp Ther. 1999 Sep;290(3):1013-8.
The alpha(1)-adrenoceptor-antagonistic and steroid 5alpha-reductase-inhibitory actions of Z-350 [(S)-4-{3-{4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-y l]propoxy}benzoyl}indole-1-yl}butyric acid hydrochloride] were investigated in rabbits and rats in vivo. Z-350 (1-30 mg/kg), administered intraduodenally, dose-dependently inhibited phenylephrine-induced increases in prostatic urethral pressure with an ED(50) value of 3.8 mg/kg in anesthetized male rabbits, whereas the effects on mean blood pressure and orthostatic hypotensive response were weaker when compared with other alpha(1)-adrenoceptor antagonists, tamsulosin and prazosin. Z-350 (1-10 mg/kg p.o.) dose-dependently inhibited the prostatic steroid 5alpha-reductase activity in rats with an ED(50) value of 2.8 mg/kg. The daily oral administration of Z-350, at >==10 mg/kg for 7 days, significantly reduced the prostatic growth induced by testosterone in castrated rats, with no effect on dihydrotestosterone-induced prostatic growth. These results indicate that Z-350 exhibited alpha(1)-adrenoceptor-antagonistic and 5alpha-reductase inhibitory actions at almost equal doses in vivo, and was expected to improve the bladder outlet obstruction associated with benign prostatic hyperplasia with smaller cardiovascular adverse effect.
在兔和大鼠体内研究了Z-350 [（S）-4-{3-{4-{1-（4-甲基苯基）-3-[4-（2-甲氧基苯基）哌嗪-1-基]丙氧基}苯甲酰基}吲哚-1-基}丁酸盐酸盐]的α（1）-肾上腺素受体拮抗作用和甾体5α-还原酶抑制作用。十二指肠内给予Z-350（1-30mg/kg），在麻醉的雄性兔中剂量依赖性地抑制去氧肾上腺素诱导的前列腺尿道压力升高，ED（50）值为3.8mg/kg，而与其他α（1）-肾上腺素受体拮抗剂坦索罗辛和哌唑嗪相比，对平均血压和体位性低血压反应的影响较弱。Z-350（1-10mg/kg口服）剂量依赖性地抑制大鼠前列腺甾体5α-还原酶活性，ED（50）值为2.8mg/kg。Z-350每日口服≥10mg/kg，连续7天，可显著降低去势大鼠中睾酮诱导的前列腺生长，对二氢睾酮诱导的前列腺生长无影响。这些结果表明，Z-350在体内以几乎相等的剂量表现出α（1）-肾上腺素受体拮抗作用和5α-还原酶抑制作用，有望改善与良性前列腺增生相关的膀胱出口梗阻，且心血管不良反应较小。
