Heylen L, De Clerck F, Somers Y, Leysen J E
Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Blood Coagul Fibrinolysis. 1991 Oct;2(5):617-21. doi: 10.1097/00001721-199110000-00005.
Ridogrel, a potent thromboxane A2 (TXA2) synthase inhibitor, also has thromboxane A2 prostaglandin endoperoxide (TXA2/PG-END) receptor antagonistic properties as documented in functional studies of human platelets. In the present study, the binding affinities of the TXA2 synthase inhibitors, ridogrel, dazoxiben, dazmegrel and pirmagrel, and the TXA2/PG-END receptor antagonists, GR32191, L670596, SQ29548, ICI159995, AH69212 and sulotroban, for the TXA2/PG-END receptor labelled with [3H]SQ29548 on intact human platelets were assessed. The potencies of the TXA2/PG-END receptor antagonists to inhibit specific [3H]SQ29548 binding to intact human platelets ranged between 1.2 nM and 6,200 nM and corresponded to the ability of the drugs to suppress human platelet aggregation induced by TXA2/PG-END receptor stimulation with U46619 and collagen. The TXA2 synthase inhibitors dazoxiben, dazmegrel and pirmagrel could not inhibit specific [3H]SQ29548 binding to intact human platelets, tested up to 10(-5) M, nor suppress human platelet aggregation, indicating lack of any receptor antagonistic properties. Ridogrel, however, directly bound to the TXA2/PG-END receptor with micromolar affinity (IC50 = 5.2 microM) and inhibited U46619-27, or collagen-induced platelet aggregation, with ED50-values of 27 microM and 4.7 microM respectively. The present study thus demonstrates that antagonism by ridogrel of TXA2/PG-END receptor activation on platelets as defined in functional tests, coincides with inhibition of specific ligand binding to the receptors.
利多格雷是一种强效血栓素A2（TXA2）合酶抑制剂，在人体血小板功能研究中也具有血栓素A2前列腺素内过氧化物（TXA2/PG-END）受体拮抗特性。在本研究中，评估了TXA2合酶抑制剂利多格雷、达唑氧苯、达美格雷和吡马格雷，以及TXA2/PG-END受体拮抗剂GR32191、L670596、SQ29548、ICI159995、AH69212和舒洛地班对完整人体血小板上用[3H]SQ29548标记的TXA2/PG-END受体的结合亲和力。TXA2/PG-END受体拮抗剂抑制[3H]SQ29548与完整人体血小板特异性结合的效力在1.2 nM至6200 nM之间，与这些药物抑制U46619和胶原刺激TXA2/PG-END受体诱导的人体血小板聚集的能力相对应。TXA2合酶抑制剂达唑氧苯、达美格雷和吡马格雷在高达10^(-5) M的浓度下测试时，不能抑制[3H]SQ29548与完整人体血小板特异性结合，也不能抑制人体血小板聚集，表明它们缺乏任何受体拮抗特性。然而，利多格雷以微摩尔亲和力（IC50 = 5.2 microM）直接与TXA2/PG-END受体结合，并分别以27 microM和4.7 microM的ED50值抑制U46619或胶原诱导的血小板聚集。因此，本研究表明，在功能测试中所定义的利多格雷对血小板上TXA2/PG-END受体激活的拮抗作用，与抑制配体与受体的特异性结合相吻合。
