Ahn C H, Shams G, Schotzinger R L, Miller D D, Feller D R
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.
Proc Soc Exp Biol Med. 1990 Jun;194(2):149-56. doi: 10.3181/00379727-194-43071.
The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and alpha-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD2 values) was R(-)-epinephrine (6.3) greater than R(-)-NE (5.9) greater than (+/-)-erythro-cobefrin (5.3) greater than S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) greater than epinine (4.4) greater than S(+)-alpha-methyldopamine (4.3) = R(-)-alpha-methyldopamine (4.3) greater than (+/-)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyl-dopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (+/-)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) greater than S(+)-alpha-methyldopamine (5.0) greater than dopamine (4.6) = R(-)-alpha-methyldopamine (4.4) greater than or equal to S(+)-NE (4.3) greater than N-isopropyldopamine (4.1) greater than S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E1 (PGE1) (0.1 microM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE1 inhibition of ADP aggregation. Phentolamine blocked these alpha 2-adrenoceptor-mediated actions against PGE1 on ADP aggregation. The rank order of potency for the reversal of PGE1-mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet alpha 2-adrenoceptors are in agreement with the Easson-Stedman hypothesis and other alpha-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were alpha 2-adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with alpha 2-adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.
研究了可乐定、肾上腺素异构体、去甲肾上腺素（NE）、异丙肾上腺素、考贝弗林和α-甲基多巴胺及其相关脱氧类似物（去甲伪麻黄碱、多巴胺、N-异丙基多巴胺）对人血小板的浓度依赖性作用。聚集效力（pD2值）的排序为：R(-)-肾上腺素（6.3）＞R(-)-NE（5.9）＞(±)-赤藓糖型考贝弗林（5.3）＞S(+)-肾上腺素（4.7）= S(+)-NE（4.7）=可乐定（4.7）=多巴胺（4.6）＞去甲伪麻黄碱（4.4）＞S(+)-α-甲基多巴胺（4.3）= R(-)-α-甲基多巴胺（4.3）＞(±)-苏阿糖型考贝弗林（3.7）。异丙肾上腺素异构体和N-异丙基多巴胺作为激动剂无活性。在16份富血小板血浆制剂中的9份中，R(-)-肾上腺素、R(-)-NE和(±)赤藓糖型考贝弗林是激动剂，其余类似物可阻断R(-)-NE诱导的聚集，抑制效力（pKB值）的排序为：可乐定（6.2）＞S(+)-α-甲基多巴胺（5.0）＞多巴胺（4.6）= R(-)-α-甲基多巴胺（4.4）≥ S(+)-NE（4.3）＞N-异丙基多巴胺（4.1）＞S(+)-异丙肾上腺素（3.7）= R(-)-异丙肾上腺素（3.5）。每种化合物还能够逆转前列腺素E1（PGE1）（0.1微摩尔）诱导的对ADP最大聚集反应的阻断。在高浓度时，R(-)-异丙肾上腺素在逆转PGE1对ADP聚集的抑制方面比S(+)-异构体或脱氧类似物N-异丙基多巴胺更有效。酚妥拉明阻断了这些α2-肾上腺素受体介导的针对PGE1对ADP聚集的作用。这些儿茶酚胺逆转PGE1介导的对ADP聚集抑制的效力排序与血小板聚集的情况相似。我们的结果表明：（i）儿茶酚胺与血小板α2-肾上腺素受体相互作用的立体化学要求与伊登-斯特德曼假说及其他α-肾上腺素受体组织一致；（ii）在R-构型中缺乏苄基羟基和/或具有N-异丙基的儿茶酚胺是α2-肾上腺素受体拮抗剂；（iii）可乐定与儿茶酚胺在与α2-肾上腺素受体相互作用方面产生的定量反应不同；（iv）对于这一系列化合物，血小板腺苷酸环化酶的抑制与肾上腺素诱导的聚集反应的抑制相关。
