Characterization of a new compound, S-145, as a specific TXA2 receptor antagonist in platelets.

S-145, a newly synthesized thromboxane A2 (TXA2) receptor antagonist, was investigated for its effects on platelet TXA2 receptors. In rat washed platelets, S-145 (100 nM) completely suppressed both U46619-induced shape change and collagen-induced shape change and aggregation, whereas aggregation responses provoked by ADP and thrombin were unaffected by S-145. S-145 had no effect on the cAMP levels in rat platelets as well as no inhibitory activity for the bindings of 3H-PGE1, 3H-Iloprost, 3H-PGD2 and 3H-PGF2 alpha to rat platelet membranes. TXB2 formation was not affected by S-145 (10 microM) in rat washed platelets. S-145 antagonized not only the collagen-induced aggregation but also the binding of 3H-U46619 in rat washed platelets with stereospecificity and high potency, which exerted an IC50 of 4.7 nM or a Ki of 2.5 nM, respectively. The potent activity of S-145 in inhibition of 3H-U46619 binding to crude platelet membranes was seen in rat as well as rabbit and human. These results demonstrate that S-145 is a highly potent and selective antagonist for platelet TXA2 receptors.