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.
Hanasaki
K
K
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Arita
H
H
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013045:Species Specificity; D013929:Thromboxane B2 / Q000096:biosynthesis
D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D005229:Fatty Acids, Monounsaturated; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C056566:S 145; D013929:Thromboxane B2; D000242:Cyclic AMP