SQ-27986 inhibition of platelet aggregation is mediated through activation of platelet prostaglandin D2 receptors.
SQ-27986, a oxabicycloheptane derivative, potently inhibits ADP-, collagen- and arachidonic acid-induced platelet aggregation in human platelet-rich plasma. Human platelet aggregation induced by ADP is inhibited by SQ-27986 (EC50 = 22nM), and the inhibitory action of SQ-27986 can be prevented with N-0164, a PGD2 antagonist. By comparison, ADP-induced rat platelet aggregation is unaffected by SQ-27986 (IC50 greater than 80 microM). Washed human platelets treated with SQ-27986 exhibit elevated cAMP levels and activated cAMP-dependent protein kinase. Elevation of platelet cAMP levels (greater than 4 fold basal) and activation of the cAMP-dependent protein kinase (greater than 4 fold) are observed with SQ-27986 concentrations above 100 nM. The SQ-27986-induced elevation of cAMP can be prevented by N-0164. Lysed platelets treated with SQ-27986 showed stimulated adenylate cyclase activity. SQ-27986 competes with [3H]prostaglandin D2 binding to isolated platelet membranes (EC50 for SQ-27986 is 20 nM, which was more potent than cold PGD2 itself). Radiolabeled Iloprost binding is virtually unaffected by SQ-27986 (EC50 greater than 100 microM), indicating that SQ-27986 does not interact with platelet prostacyclin receptors. These studies indicate that SQ-27986 inhibits platelet aggregation by activating platelet adenylate cyclase via stimulation of platelet PGD2 receptors.
Seiler
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Bristol-Myers Squibb Co., Wallingford, CT 06492.
Brassard
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Federici
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D000244:Adenosine Diphosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood / Q000494:pharmacology; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors / Q000097:blood; D011494:Protein Kinases / Q000097:blood; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000502:physiology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C012641:N 0164; D000244:Adenosine Diphosphate; C066023:SQ 27986; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor