Romstedt K J, Shin Y, Shams G, Doyle K, Tantishaiyakul V, Clark M T, Adejare A, Hamada A, Miller D D, Feller D R
Division of Pharmacology, College of Pharmacy, Ohio State University, Columbus 43210.
Biochem Pharmacol. 1993 Dec 3;46(11):2051-9. doi: 10.1016/0006-2952(93)90647-f.
Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.
曲美喹诺（TMQ）是一种非前列腺素类化合物，它能阻断前列腺素H2/血栓素A2（TXA2）受体介导的反应，这些反应由前列腺素（PG）H2类似物U46619在人血小板和大鼠主动脉中引发。环氟取代的TMQ类似物选择性拮抗由U46619、花生四烯酸、胶原、ADP或肾上腺素诱导的PG依赖性人血小板活化；并且作为凝血酶或细菌磷脂酶C介导的非PG依赖性反应的抑制剂，其效力约低300倍。对于PG依赖性途径的每种诱导剂，抑制效力的排序相同（TMQ > 8-氟-TMQ > 5-氟-TMQ）。碘取代产生了针对U46619诱导的血小板活化的类似拮抗排序（TMQ > 8-碘-TMQ > 5-碘-TMQ），并且所有TMQ类似物均抑制全血以及富含血小板血浆中的血小板聚集。TMQ类似物对特异性[3H]SQ 29,548结合的抑制与对U46619功能反应的抑制高度相关。使用TMQ类似物与大鼠血小板进行的放射性配体结合实验表明，与人类血小板相比，不存在种间差异。作为U46619诱导的血管收缩的拮抗剂，在大鼠胸主动脉中，氟化（但非碘化）TMQ类似物的抑制效力排序发生变化，8-氟-TMQ > TMQ > 或 = 5-氟-TMQ。这些发现表明，TMQ类似物抗血小板作用的主要机制与TXA2受体位点的阻断有关，并且环卤代TMQ类似物可区分血管平滑肌和血小板中TXA2介导的功能反应。
