ELUCIDATION OF THE INSURMOUNTABLE NATURE OF AN ANGIOTENSIN RECEPTOR ANTAGONIST, SC-54629

SC-54628 -yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one] and its 1- (2,6-dimethylphenyl)-2H-imidazol-2-one derivative SC-54629 were potent inhibitors of I-125-angiotensin II (I-125-All) binding to rat adrenal cortex angiotensin type 1 (AT(1)) receptors. SC-54628 and SC-54629 an tagonized All-induced contraction of rabbit vascular smooth muscle in a surmountable fashion and an insurmountable fashion, respectively. Bi nding experiments with SC-54629 were undertaken to determine the natur e of receptor interaction, which might explain the insurmountable mode of antagonism of SC-54629. The presence of a high concentration of SC -54629 did not affect the dissociation of membrane-bound I-125-All ind uced by an excess of unlabeled All, indicating that the antagonist bin ds to the agonist binding site and not an allosteric domain. Incubatio n of adrenal cortex membranes with SC-54629 decreased the density of I -125-All binding sites. When incubation of the SC-54629-treated membra nes with radiolabeled All was prolonged, the SC-54629-induced decrease in AT(1) receptor density was attenuated, suggesting that binding of the antagonist is slowly reversible. Furthermore, the dissociation of [H-3]SC-54629 was 5-fold slower than that of I-125-All bound to AT(1) receptors. These results suggest that the insurmountable antagonism of All by SC-54629 is most likely due to the slow reversibility of SC-54 629 binding to the AT(1) receptor.