Elucidation of the insurmountable nature of an angiotensin receptor antagonist, SC-54629.
SC-54628 [1-(2-methylphenyl)-4-butyl-1,3-dihydro-3-[[6-[2-(1H- tetrazol-5-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 125I-angiotensin II (125I-AII) binding to rat adrenal cortex angiotensin type 1 (AT1) receptors. SC-54628 and SC-54629 antagonized AII-induced contraction of rabbit vascular smooth muscle in a surmountable fashion and an insurmountable fashion, respectively. Binding experiments with SC-54629 were undertaken to determine the nature 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 125I-AII induced by an excess of unlabeled AII, indicating that the antagonist binds to the agonist binding site and not an allosteric domain. Incubation of adrenal cortex membranes with SC-54629 decreased the density of 125I-AII binding sites. When incubation of the SC-54629-treated membranes with radiolabeled AII was prolonged, the SC-54629-induced decrease in AT1 receptor density was attenuated, suggesting that binding of the antagonist is slowly reversible. Furthermore, the dissociation of [3H]SC-54629 was 5-fold slower than that of 125I-AII bound to AT1 receptors. These results suggest that the insurmountable antagonism of AII by SC-54629 is most likely due to the slow reversibility of SC-54629 binding to the AT1 receptor.
Department of Cardiovascular Diseases Research, G.D. Searle & Co., St. Louis, Missouri 63167.
G M
GM
Olins
S T
ST
Chen
E G
EG
McMahon
M A
MA
Palomo
D B
DB
Reitz
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001665:Binding Sites; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D011945:Receptors, Angiotensin / Q000819:agonists / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011945:Receptors, Angiotensin; C091712:SC 54628; C091711:SC 54629; D000804:Angiotensin II