IN-VITRO PHARMACOLOGICAL CHARACTERIZATION OF A NEW SELECTIVE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST, UR-7280

UR-7280 ,1'-biphenyl-4-yl]methyl]-1H-pyrazole-4-carboxylic acid) is a new and potent angiotensin AT(1)-selective receptor antagonist. Bindin g studies in rat liver membranes showed that UR-7280 is an apparently competitive antagonist. However, in rabbit aorta this compound antagon ized the angiotensin II-induced contractile response in an insurmounta ble way, causing a significant reduction of the maximal response. Addi tional binding studies evidenced that UR-7280 has a slowly reversible binding profile, consistent with its functional properties in rabbit a orta. The results obtained with a series of structural analogues of UR -7280 demonstrated a relationship between the size of the pyrazole 3-s ubstituent and the surmountable or insurmountable mode of antagonism, indicating that this position may play a key role in the interaction b etween the antagonist and the angiotensin AT(1) receptor.