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Elucidation of the insurmountable nature of an angiotensin receptor antagonist, SC-54629

GM Olins, ST Chen, EG McMahon, MA Palomo and DB Reitz

Department of Cardiovascular Diseases Research, G.D. Searle & Co., St. Louis, Missouri 63167.

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.

Volume 47, Issue 1, pp. 115-120, 01/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




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Copyright © 1995 by the American Society for Pharmacology and Experimental Therapeutics