Timmermans P B, de Jonge A, Thoolen M J, Wilffert B, Batink H, van Zwieten P A
J Med Chem. 1984 Apr;27(4):495-503. doi: 10.1021/jm00370a011.
Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)
针对一系列11种α-肾上腺素能拮抗剂和35种化学结构各异的激动剂，得出了其对α1-和α2-肾上腺素能受体的体外亲和力（分别为大鼠脑膜中[3H]哌唑嗪和[3H]可乐定的特异性结合位点）与体外及体内α1/α2-肾上腺素能受体激动剂/拮抗剂活性之间的定量关系。对于拮抗剂，α1/α2结合选择性比率与体外（兔离体肺动脉：α1-肾上腺素能受体诱导的血管收缩拮抗作用及α2-肾上腺素能受体诱发的递质释放促进作用）和体内（去脑正常血压大鼠中α1-和α2-肾上腺素能受体介导的血管收缩拮抗作用）评估的功能性α1/α2阻断选择性比率最显著相关。这些结果表明，拮抗剂的体外α1-和α2-肾上腺素能受体结合亲和力提供了有关其针对激动剂的功能性α1-和α2-肾上腺素能受体阻断效力的充分信息。对于激动剂，中枢性α2-肾上腺素能受体引发的降压活性与α1-肾上腺素能受体结合亲和力无关，而最显著地表现为对α2-肾上腺素能受体的亲和力以及对log P'（正辛醇/缓冲液；pH 7.4；37℃）的抛物线依赖性。回归中log P'的相关性可通过放射性配体置换实验中膜结合α2-肾上腺素能受体与完整动物中枢髓质（降压）α2-肾上腺素能受体的可及性差异来解释。相反，已知α1-和α2-肾上腺素能受体起作用的激动剂的升压效力，其α1-和α2-肾上腺素能受体的亲和力参数是较差的描述指标。纳入个体结合参数和两个变量组合的相关性仅达到中等显著水平。（摘要截短于250字）
