Gm. Olins et al., ELUCIDATION OF THE INSURMOUNTABLE NATURE OF AN ANGIOTENSIN RECEPTOR ANTAGONIST, SC-54629, Molecular pharmacology, 47(1), 1995, pp. 115-120
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.