Difluorothromboxane A2 and stereoisomers: Stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels

The present study reports on the selective effects on human platelets and canine saphenous veins of four stable difluorinated analogues and thromboxane A2 (TXA2), in which the characteristic 2,6-dioxa[3.1.1]bicycloheptane structure of TXA2 has been retained. The four compounds differ in their stereochemistry of the 5,6 double bond and/or the 15-hydroxyl group. Only 10,10-difluoro-TXA2 (compound I) with the natural stereochemistry of TXA2 was an agonist in both platelets and canine saphenous veins. (15R)-10,10-Difluoro-TXA2 (compound II), (5E)-10,10-difluoro-TXA2 (compound III), and (5E,15R)-10,10-difluoro-TXA2 (compound IV) were antagonists of platelet aggregation stimulated by compound I. However, compounds II, III, and IV stimulated contraction of canine saphenous veins. All four compounds could displace the TXA2/prostaglandin H2 antagonist 9,11-dimethylmethano-11,12-methano-16-(3-125I-4-hydroxyphenyl)-13,14-dihydro-13-aza-15αβ-ω-tetranor-TXA2 from its platelet receptor. These results support the existence of two subtypes of TXA2/prostaglandin H2 receptors and emphasize the importance of the stereochemical requirements of these TXA2 analogues for interaction with these receptors. These stable fluorinated TXA2 analogues should prove useful tools for the further characterization of these and other TXA2/prostaglandin H2 receptors