Ahn C H, Hamada A, Miller D D, Feller D R
Biochem Pharmacol. 1986 Nov 15;35(22):4095-102. doi: 10.1016/0006-2952(86)90034-1.
Adrenoceptor-mediated effects of the enantiomers of optically active imidazoline, 2-(3,4,alpha-trihydroxybenzyl imidazoline (catecholimidazoline; CI), and norepinephrine (NE), and the corresponding desoxy derivatives, 2-(3,4-dihydroxybenzyl)imidazoline (desoxy-CI) and dopamine, have been investigated in human platelets. Differences between responsiveness of platelets from donor to donor were observed in the presence of the isomers and the desoxy analogs of NE and CI. In certain platelet preparations, all compounds gave concentration-dependent stimulatory responses, whereas in other preparations, only R(-)-NE and R(-)-CI were inducers of platelet aggregation and serotonin release. The rank order of stimulatory potencies (EC50; microM) for CI and NE was R(-)-NE (1.3) greater than R(-)-CI (7.5) greater than S(+)-NE (19) = S(+)-CI (20) = dopamine (22) greater than desoxy-CI (greater than 35). Unlike R(-)-CI, both S(+)-CI and desoxy-CI were either agonists or antagonists of human platelet function. In preparations unresponsive to the S(+)-isomers or desoxy analogs, the potencies (EC50) for R(-)-NE and R(-)-CI were 1.7 and 7.7 microM respectively. The corresponding inactive CIs [S(+)-CI and desoxy-CI] were inhibitors of both primary and secondary phases of aggregation and serotonin release responses to R(-)-CI and R(-)-NE, respectively. In contrast, the aggregation responses to ADP, arachidonic acid or U46619 were not blocked by S(+)-CI or desoxy CI. The rank order of inhibitory potencies for selected alpha-adrenoceptor agents against R(-)-NE was phentolamine greater than clonidine greater than desoxy-CI greater than S(+)-CI. Moreover, the relative inhibitory potencies of phentolamine and desoxy-CI against aggregation responses to R(-)-NE and R(-)-CI, respectively, were the same. These results suggest that the enantiomers and desoxy derivatives of CI and NE mediate their effects in human platelets by an interaction with alpha-adrenoceptors; catecholamines and imidazolines interact with the same alpha-adrenoceptors in human platelets; the stereochemical requirements of both chemical classes for stimulatory activity in human platelets adhere to the Easson-Stedman hypothesis in this alpha 2-adrenoceptor system; and desoxy-CI possessed the highest potency as an antagonist of alpha-adrenoceptors which suggests that the hydroxy group at the benzylic carbon atom of these imidazolines may not be required for maximal binding to adrenoceptors in platelets.
在人血小板中研究了光学活性咪唑啉对映体、2-(3,4,α-三羟基苄基)咪唑啉（儿茶酚咪唑啉；CI）和去甲肾上腺素（NE）以及相应的脱氧衍生物2-(3,4-二羟基苄基)咪唑啉（脱氧-CI）和多巴胺的肾上腺素能受体介导的效应。在NE和CI的异构体及脱氧类似物存在的情况下，观察到不同供体的血小板反应性存在差异。在某些血小板制剂中，所有化合物均产生浓度依赖性刺激反应，而在其他制剂中，只有R(-)-NE和R(-)-CI可诱导血小板聚集和5-羟色胺释放。CI和NE的刺激效力（EC50；微摩尔）的排序为：R(-)-NE（1.3）＞R(-)-CI（7.5）＞S(+)-NE（19）= S(+)-CI（20）=多巴胺（22）＞脱氧-CI（＞35）。与R(-)-CI不同，S(+)-CI和脱氧-CI均为人血小板功能的激动剂或拮抗剂。在对S(+)-异构体或脱氧类似物无反应的制剂中，R(-)-NE和R(-)-CI的效力（EC50）分别为1.7和7.7微摩尔。相应的无活性CI[S(+)-CI和脱氧-CI]分别是对R(-)-CI和R(-)-NE的聚集和5-羟色胺释放反应的初级和次级阶段的抑制剂。相比之下，S(+)-CI或脱氧-CI并未阻断对ADP、花生四烯酸或U46619的聚集反应。所选α-肾上腺素能受体拮抗剂对R(-)-NE的抑制效力排序为：酚妥拉明＞可乐定＞脱氧-CI＞S(+)-CI。此外，酚妥拉明和脱氧-CI分别对R(-)-NE和R(-)-CI聚集反应的相对抑制效力相同。这些结果表明，CI和NE的对映体及脱氧衍生物通过与α-肾上腺素能受体相互作用在人血小板中介导其效应；儿茶酚胺和咪唑啉在人血小板中与相同的α-肾上腺素能受体相互作用；在该α2-肾上腺素能受体系统中，这两类化学物质在人血小板中产生刺激活性的立体化学要求符合伊登-斯特德曼假说；脱氧-CI作为α-肾上腺素能受体拮抗剂具有最高效力，这表明这些咪唑啉苄基碳原子上的羟基对于在血小板中与肾上腺素能受体的最大结合可能并非必需。
