Lack of cross‐desensitization between structurally dissimilar α‐adrenoceptor agonists
Lack of cross‐desensitization between structurally dissimilar α‐adrenoceptor agonists
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结构不同的 α-肾上腺素受体激动剂之间缺乏交叉脱敏作用
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发表时间：
1977
期刊：
影响因子：
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通讯作者：
P. Patil
中科院分区：
文献类型：
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作者：
R. Ruffolo;B. Turowski;P. Patil
最近，我们描述了[？可逆的α-肾上腺素受体拮抗剂H]二氢氮杂嘌呤与大鼠输精管的粗膜部分的反应（Ruffolo，米勒等人，1976 a; Ruffolo，Fowble等人，1976 b）。[3 H]二氢扎帕汀结合到具有许多预期为α-肾上腺素受体的特征的位点。特别是，所有α-肾上腺素受体拮抗剂和咪唑啉类激动剂均抑制[3 H]二氢氮杂卓的特异性结合，结合位点的亲和力与已知受体亲和力之间具有良好的相关性。然而，苯乙胺类的直接作用激动剂（即去甲肾上腺素的结构类似物）反而增加了结合。假设变构效应来解释这些结果，这些结果也与Kalsner的药理学实验一致（1970，1973）。苯乙胺和咪唑啉类激动剂之间的差异效应与[3 H]二氢氮杂卓结合，结合这两个类之间的显着的结构差异，促使我们提出，咪唑啉在不同的网站上的受体比苯乙胺相互作用。AriCns和Simonis（1964）提出了一个类似的假设，涉及激动剂和结构不同的拮抗剂在α-肾上腺素受体上的不同相互作用位点。我们相信，我们的受体脱敏药理学实验为咪唑啉类和苯乙胺类激动剂在肾上腺素受体上存在不同的相互作用位点提供了证据。咪唑啉激动剂相对长效，重复给药后产生受体脱敏（Mujic &货车Rossum，1965; Sanders，米勒& Patil，1975）。据推测，如果咪唑啉和直接作用的苯乙胺存在一个共同的结合位点或结合模式，那么α-肾上腺素受体对咪唑啉的脱敏将导致对其他咪唑啉以及苯乙胺的脱敏。相反，如果存在不同的相互作用位点，咪唑啉和苯乙胺之间的交叉脱敏可能不会发生。据信脱敏实验可用于区分不同的受体（Barsoum & Gaddum，1935; Waud，1968; Schild，1973）。因此，存在这样的可能性，即该程序也可以区分同一受体蛋白上的不同相互作用位点。从雄性白化病大鼠中分离输精管，并固定在恒温（37.5”）器官浴中以记录等长药物诱导的收缩
Recently, we have described the binding of [?H]dihydroazapetine, a reversible a-adrenoceptor antagonist, to a crude membrane fraction from the rat vas deferens (Ruffolo, Miller & others, 1976a; Ruffolo, Fowble & others, 1976b). [3H]Dihydrozapetine binds to a site with many characteristics expected for the a-adrenoceptor. In particular, all a-adrenoreceptor antagonists, and those agonists of the imidazoline class, inhibited specific binding of [3H]dihydroazapetine with excellent correlation between affinity for the binding site and known affinity for the receptor. Direct-acting agonists of the phenethylamine class (i.e. structural analogues of noradrenaline), however, paradoxically increased binding. An allosteric effect was postulated to explain these results which are also consistent with the pharmacological experiments of Kalsner (1970, 1973). The differential effects between agonists of the phenethylamine and imidazoline classes with respect to [3H]dihydroazapetine binding, combined with the marked structural dissimilarities between the two classes, prompted us to propose that imidazolines interact at a different site on the receptor than the phenethylamines. A similar postulation involving different sites of interaction on the a-adrenoceptor for agonists and structurally dissimilar antagonists has been proposed by AriCns & Simonis (1964). We believe that our pharmacological experiments on receptor desensitization furnish evidence for the existence of different sites of interaction on the cr-adrenoceptor for agonists of the imidazoline and phenethylamine classes. The imidazoline agonists are relatively long-acting and produce receptor desensitization upon repeated administration (Mujic & van Rossum, 1965; Sanders, Miller & Patil, 1975). It was reasoned that if one common binding site, or mode of binding, existed for imidazolines and directly-acting phenethylamines, then desensitization of the a-adrenoceptor to an imidazoline would result in desensitization to other imidazolines as well as the phenethylamines. Conversely, if different sites of interaction were to exist, cross-desensitization between imidazolines and phenethylamines might not occur. It is believed that desensitization experiments may be useful in distinguishing between different receptors (Barsoum & Gaddum, 1935; Waud, 1968; Schild, 1973). The possibility exists, therefore, that the procedure may also discriminate between different sites of interaction on the same receptor protein. Vasa deferentia were isolated from male albino rats and mounted in constant temperature (37.5") organ baths for recording isometric drug-induced contractions