Timmermans P B, de Jonge A, van Meel J C, Slothorst-Grisdijk F P, Lam E, van Zwieten P A
J Med Chem. 1981 May;24(5):502-7. doi: 10.1021/jm00137a006.
The agonist selectivities of central (medullary) and peripheral (vascular) alpha-adrenoceptors were compared in order to investigate a possible similarity among these two alpha-adrenoceptor populations. Linear regression equations were derived between the alpha-adrenergic potencies, mediated by these two types of alpha-adrenoceptors for 21 structurally dissimilar alpha-adrenoceptor agonists. Hypotensive potency after intravenous administration to anesthetized, normotensive rats was determined as a measure of central alpha-adrenergic activity and expressed as pC25, obtained from log dose-response curves. Peripheral alpha-adrenergic potency was quantified by means of the hypertensive effect elicited in pithed, normotensive rats after intravenous injections, yielding pC60 as the biological variable. A most significant linear relationship was generated between central hypotensive activity (pC25) and peripheral hypertensive potency (pC60), provided that log P' (octanol/buffer; pH 7.4, 37 degrees C) was included into the regression in a parabolic form. This result indicates that the central (medullary) alpha-adrenoceptors and the peripheral (vascular) alpha-adrenoceptor sites, which are excited by the drugs in question, make identical demands upon their agonists. The difference in accessibility to these peripheral and central alpha-adrenoceptor populations is adequately accounted for by a parabolic description in log P'. The apparent contradiction of this finding with the suggestion that central, hypotensive alpha-adrenoceptors are of the alpha 2 type and peripheral, vascular alpha-adrenoceptors belong to the alpha 1 subpopulation is discussed. The recent identification of an additional subclass of postsynaptic, vascular alpha 2-adrenoceptors and the lack of pronounced differential stimulating activity of the agonists at peripheral alpha-adrenoceptors may explain the present findings and clarify the paradox.
为了研究这两种α-肾上腺素能受体群体之间可能存在的相似性，对中枢（髓质）和外周（血管）α-肾上腺素能受体的激动剂选择性进行了比较。针对21种结构不同的α-肾上腺素能激动剂，推导了由这两种类型的α-肾上腺素能受体介导的α-肾上腺素能效力之间的线性回归方程。对麻醉的正常血压大鼠静脉给药后的降压效力被确定为中枢α-肾上腺素能活性的指标，并表示为pC25，它是从对数剂量反应曲线中获得的。外周α-肾上腺素能效力通过静脉注射后在去脑的正常血压大鼠中引起的升压效应进行量化，得到pC60作为生物学变量。如果将log P'（辛醇/缓冲液；pH 7.4，37℃）以抛物线形式纳入回归，则中枢降压活性（pC25）和外周升压效力（pC60）之间产生了非常显著的线性关系。这一结果表明，所研究药物所兴奋的中枢（髓质）α-肾上腺素能受体和外周（血管）α-肾上腺素能受体位点对其激动剂有相同的要求。log P'中的抛物线描述充分解释了这些外周和中枢α-肾上腺素能受体群体在可及性上的差异。讨论了这一发现与以下观点的明显矛盾，即中枢降压α-肾上腺素能受体为α2型，外周血管α-肾上腺素能受体属于α1亚群。最近鉴定出突触后血管α2-肾上腺素能受体的另一个亚类，以及激动剂在外周α-肾上腺素能受体上缺乏明显的差异刺激活性，可能解释了目前的发现并澄清了这一矛盾。
