Receptor binding properties of the new and specific thromboxane receptor antagonist Bay U 3405.
Human platelet membranes were used to characterize the receptor binding properties of the specific thromboxane receptor antagonist 3H-SQ 29548 and the displacement of 3H-SQ 29548 from its binding site by the new thromboxane receptor antagonist Bay u 3405. The specific binding of 3H-SQ 29548 was saturable with an association rate constant of 1 x 10(-11) mol-1 min-1 and a dissociation rate constant of 0.032 min-1. Nonspecific binding of 3H-SQ 29548 was below 10%. When Scatchard plot analysis was performed on equilibrium saturation binding the kD was 69 nmol/l and the Bmax was calculated as 3.9 pmol/mg membrane protein. 3H-SQ 29548 was dose dependently displaced from its binding site by addition of increasing concentrations of Bay u 3405 yielding an IC50 value of 68 +/- 12 nmol/l, being not significantly different from the IC50 of nonlabelled SQ 29548 (38 +/- 13 nmol/l). The results show that Bay u 3405 is a potent and specific thromboxane receptor antagonist, displacing 3H-SQ 29548 from its binding site on human platelet membranes with IC50 values being not significantly different. These receptor binding properties and the long biological half life reported in vivo make Bay u 3405 a promissing compound for the treatment of human cardiovascular diseases.
Darius
H
H
Department of Medicine II, Johannes Gutenberg-University, Mainz, Germany.
Michael-Hepp
J
J
Meyer
J
J
D001667:Binding, Competitive / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002227:Carbazoles / Q000378:metabolism / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002227:Carbazoles; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; D013928:Thromboxane A2; C045749:SQ 29548; C063119:ramatroban