Characterization of (5Z)-7-[3-endo-[(4-iodophenylsulfonyl) amino] -bicyclo[2.2.1]hep-2-exo-yl]heptenoic acid (IS-145) as an antagonist for the study of thromboxane A2 receptor.
(5Z)-7-[3-endo-[(4-iodophenylsulfonyl) amino]bicyclo[2.2.1]-hep-2-exo-yl] heptenoic acid (IS-145) was characterized on its suitability for the study of thromboxane A2 (TXA2) receptor. Both the I-125 and I-127 analogs are very potent TXA2 antagonist. The I-127 analog interacted with the receptor specifically as shown by the displacement of [3H]-SQ29548 from its binding sites on human platelet membranes in a dose dependent manner. It also elicited specific biological responses by inhibiting I-BOP induced platelet aggregation. However, they failed to inhibit those induced by platelet activating factor. Moreover, it interfered with the TXA2 receptor activated signal transduction system by inhibiting I-BOP induced increase in GTP-gamma-[35S] binding and GTPase activity. These data indicated that IS-145 was indeed a specific antagonist. The I-125 analog was used as a radioactive ligand to characterize TXA2 receptor in human platelet membranes. The binding was found to be saturable, reversible and specific with a KD of 5.8 nM and a Bmax of 1.9 pmol/mg protein.
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Division of Medicinal Chemistry & Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Tai
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D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; C082371:IS 145; D006160:Guanosine Triphosphate; C045749:SQ 29548; D020558:GTP Phosphohydrolases