In vitro pharmacological characterization of a new selective angiotensin AT1 receptor antagonist, UR-7280.
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.
De Arriba
A F
AF
Pharmacology Laboratory, Research Center, J. Uriach & Cia S.A., Barcelona, Spain.
Gómez-Casajús
L A
LA
Cavalcanti
F
F
Almansa
C
C
García-Rafanell
J
J
Forn
J
J
D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D011720:Pyrazoles; D013777:Tetrazoles; C105773:UR 7280; D000804:Angiotensin II