HALOGEN-SUBSTITUTED TRIMETOQUINOL ANALOGS AS THROMBOXANE A(2) RECEPTOR ANTAGONISTS IN PLATELETS AND AORTA

Trimetoquinol (TMQ) is a non-prostanoid compound that blacks prostagla ndin H-2/thromboxane A(2) (TXA(2)) receptor-mediated responses initiat ed by a prostaglandin (PG) H-2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagoniz ed PC-dependent human platelet activation induced by U46619, arachidon ic acid, collagen, ADP or epinephrine; and were about 300-fold less po tent as inhibitors of PC-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PC-dependent pathw ay, 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-iod o-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregatio n in whole blood as well as in platelet-rich plasma. Inhibition of spe cific [H-3]SO 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding exp eriments using TMQ analogs with rat platelets showed no interspecies d ifference in comparison with human platelets. The rank order of inhibi tory potencies for the fluorinated (but not iodinated) TMQ analogs cha nged in rat thoracic aorta with 8-fluoro-TMQ > TMQ greater than or equ al to 5-fluoro-TMQ as antagonists of U46619-induced vascular contracti on. These findings demonstrate that the primary mechanism of antiplate let action of TMQ analogs is related to a blockade of TXA(2) receptor sites, and ring-halogenated TMQ analogs distinguish between TXA(2)-med iated functional responses in vascular smooth muscle and platelets.