James M K, Leighton H J
Molecular Pharmacology Department, Glaxo Research Laboratories, Glaxo Inc., Research Triangle Park, North Carolina.
J Pharmacol Exp Ther. 1987 Sep;242(3):772-6.
Sgd 101/75 [2-(2-methylindazol-4-imino)-imidazolidine hydrochloride] is an alpha 1 adrenoceptor agonist that shows a greater sensitivity to receptor alkylation with phenoxybenzamine (POB) than norepinephrine (NE) (present study). J. Coates, D.G. Weetman and their co-workers have concluded that Sgd 101/75 is selective for a subtype of alpha-1 receptors, i.e., alpha-1s. The present studies have shown that Sgd 101/75 was a full agonist in the rat anococcygeus muscle and acts at alpha-1 adrenoceptors, as determined by Schild analysis of prazosin antagonism (pKB = 9.24 +/- 0.21, slope = 0.87 +/- 0.13). Alkylation experiments showed that the contractile effects of Sgd 101/75 were more sensitive to POB than the effects of NE. These experiments also allowed the determination of KA values for these agonists (Sgd 101/75 KA = 1.5 +/- 0.6 X 10(-5) M, NE KA = 2.6 +/- 1.0 X 10(-6) M). At 3 X 10(-8) M POB (10 min), the contractile effect of Sgd 101/75 was eliminated, whereas the concentration-effect curve for NE was shifted approximately one log unit to the right with a 20% decrease in maximal response. After similar POB treatment, incubation with Sgd 101/75 (60 min, 3 X 10(-6) to 3 X 10(-4) M) shifted the NE curve to the right in a concentration-dependent manner. Schild regression of these data yielded a pKB = 5.22 +/- 0.09 and slope = 0.87 +/- 0.08. This pKB (-log KB) showed that Sgd 101/75 was competing for the same receptor after POB treatment and before POB treatment (mean of -log KA = 4.92 +/- 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)
Sgd 101/75 [2-(2-甲基吲唑-4-亚氨基)-咪唑烷盐酸盐] 是一种α1肾上腺素能受体激动剂，与去甲肾上腺素（NE）相比，它对苯氧苄胺（POB）介导的受体烷基化表现出更高的敏感性（本研究）。J. 科茨、D.G. 韦特曼及其同事得出结论，Sgd 101/75对α1受体的一个亚型具有选择性，即α1s。本研究表明，Sgd 101/75在大鼠肛门尾骨肌中是一种完全激动剂，作用于α1肾上腺素能受体，这是通过对哌唑嗪拮抗作用的希尔德分析确定的（pKB = 9.24 ± 0.21，斜率 = 0.87 ± 0.13）。烷基化实验表明，Sgd 101/75的收缩效应比NE的效应对POB更敏感。这些实验还确定了这些激动剂的KA值（Sgd 101/75 KA = 1.5 ± 0.6×10−5 M，NE KA = 2.6 ± 1.0×10−6 M）。在3×10−8 M POB（10分钟）作用下，Sgd 101/75的收缩效应被消除，而NE的浓度-效应曲线向右移动约一个对数单位，最大反应降低20%。经过类似的POB处理后，用Sgd 101/75（60分钟，3×10−6至3×10−4 M）孵育使NE曲线以浓度依赖的方式向右移动。对这些数据进行希尔德回归得到pKB = 5.22 ± 0.09，斜率 = 0.87 ± 0.08。这个pKB（-log KB）表明，Sgd 101/75在POB处理后和处理前竞争的是同一受体（-log KA的平均值 = 4.92 ± 0.12）。（摘要截取自250字）
