9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogues: specific stable agonist (SQ 26, 538) and antagonist (SQ 26, 536) of the human platelet thromboxane receptor.
A newly synthesized 9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26, 536, (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I50 value of 1.7 microM. SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH2 and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A50 value of 2.5 microM. SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a Ki value of 3 microM. Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH2-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002417:Cattle; D000242:Cyclic AMP / Q000097:blood; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D015230:Prostaglandin D2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology*; D011457:Prostaglandins D / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D017482:Receptors, Thromboxane; D012669:Seminal Vesicles / Q000201:enzymology; D013930:Thromboxane-A Synthase / Q000097:blood
D001095:Arachidonic Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D011453:Prostaglandins; D011457:Prostaglandins D; D011956:Receptors, Cell Surface; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; C032408:SQ 26536; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; D015230:Prostaglandin D2