Subject(s)
Fluoresceins , Platelet Aggregation Inhibitors/analysis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Adenosine Diphosphate/pharmacology , Blood Platelets/metabolism , Fibrinogen/metabolism , Fluorescent Dyes , Humans , Inhibitory Concentration 50 , Methods , Platelet Activation/drug effects , Platelet Adhesiveness/drug effects , Platelet Aggregation Inhibitors/chemistry , Protein Binding , Spectrometry, FluorescenceABSTRACT
UR-7280 (3-tert-butyl-1-propyl-5-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT1-selective receptor antagonist. Binding studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagonized the angiotensin II-induced contractile response in an insurmountable way, causing a significant reduction of the maximal response. Additional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit aorta. The results obtained with a series of structural analogues of UR-7280 demonstrated a relationship between the size of the pyrazole 3-substituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction between the antagonist and the angiotensin AT1 receptor.
