评估药物选择性的α1肾上腺素能受体拮抗剂在前列腺α1肾上腺素能受体:绑定,功能和体内研究。

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肯尼英航,米勒,威廉姆森IJ,奥康奈尔J,查尔默斯DH,奈勒

评估药物选择性的α1肾上腺素能受体拮抗剂在前列腺α1肾上腺素能受体:绑定,功能和体内研究。

Br J杂志。1996年6月,118 (4):871 - 8。

PubMed ID

8799556 (在PubMed

]

文摘

1。α1肾上腺素能受体拮抗剂的概要的范围确定在体外对克隆人类的α1,α1 b和dα1肾上腺素能受体对大鼠主动脉noradrenaline-mediated收缩和人类前列腺癌。化合物的体内的状况确定在一个麻醉犬模型,允许对phenylephrine-mediated增加对手力量的同时评估血压和前列腺的压力。2。喹唑啉拮抗剂、哌唑嗪doxazosin alfuzosin显示高亲和力,但三种克隆人类的非选择性α1肾上腺素能受体。Indoramin, 1069显示选择性α1和α1 b相对于α1肾上腺素能受体d亚型。Rec 15/2739, 4101年世行,SL 89年,0591年,(+)和(-)- tamsulosin显示d选择性α1和α1肾上腺素能受体相对于α1 b亚型。RS 17053显示高亲和力和选择性α1肾上腺素能受体8.6 (pKi)相对于α1 b (pKi = 7.3)和α1 d亚型(pKi = 7.1)。3所示。-Tamsulosin (+) (-) -Tamsulosin, SL 89年,0591年,Rec 15/2739,把1069和17053卢比作为竞争对手出现noradrenaline-mediated收缩的大鼠主动脉的回目亲和力估计是类似于绑定在克隆人类dα1肾上腺素能受体亲和力。 The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker. SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities. The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak antagonist on human prostate (pA2 = 6.0) relative to the high affinity (pKi = 8.6) determined at cloned human alpha 1A adrenoceptors. 5. In the anaesthetized dog, in vivo pseudo "pA2' values showed that doxazosin, (+)- and (-)-tamsulosin inhibited phenylephrine-induced increases in prostatic and blood pressure with similar affinity, implying that these agents show little or no selectivity for prostatic responses in this model. SL 89,0591 and SNAP 1069 were moderately selective (3 and 6 fold respectively) for prostatic pressure relative to blood pressure. Rec 15/2739 was a more potent antagonist of phenylephrine-mediated increases in prostatic pressure ("pA2' = 8.74) compared to blood pressure ("pA2' = 7.51). 6. Data in this study suggest that the alpha 1 adrenoceptor mediating noradrenaline-induced contractions of human prostate, whilst having some of the characteristics of an alpha 1A adrenoceptor, cannot be satisfactorily aligned with cloned alpha 1A, alpha 1B or alpha 1D adrenoceptors. In addition, studies in the anaesthetized dog have shown that agents having high affinity and selectivity for prostatic alpha 1 adrenoceptors, particularly over the alpha 1D subtype, appear to inhibit phenylephrine-induced increases in prostatic pressure selectively compared to blood pressure.

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药物靶点

药物	目标	类	生物	药理作用	行动
Alfuzosin	Alpha-1A肾上腺素能受体	蛋白质	人类	是的	拮抗剂	细节
Alfuzosin	Alpha-1B肾上腺素能受体	蛋白质	人类	是的	拮抗剂	细节
Alfuzosin	Alpha-1D肾上腺素能受体	蛋白质	人类	是的	拮抗剂	细节