JPET xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chiu, A. T.
Right arrow Articles by Timmermans, P. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiu, A. T.
Right arrow Articles by Timmermans, P. B.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL

Nonpeptide angiotensin II receptor antagonists. III. Structure-function studies

AT Chiu, JV Duncia, DE McCall, PC Wong, WA Price , MJ Thoolen, DJ Carini, AL Johnson and PB Timmermans

Medical Products Department, E.I. du Pont de Nemours & Company, Wilmington, Delaware.

A series of 1-benzylimidazole-5-acetate derivatives defining the critical substituents on the phenyl ring was synthesized in order to improve on the affinity of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole- 5-acetate, sodium (S-8308) for the angiotensin II (AII) receptor. The analogs, substituted with -1-(4-carboxybenzyl) (EXP6155),-1-[4-(2- carboxybenzamido)benzyl] (EXP6159) and the 5-methylacetate of EXP6159 (EXP6803), were found to inhibit the binding of [3H]AII to AII receptors in rat adrenal cortical microsomes with 9-, 35- and 107-fold higher affinity, respectively, than that of S-8308 (IC50, 15 X 10(-6) microM). Scatchard analysis of the [3H]AII binding revealed that in the presence of EXP6155 (10(-6) M), the dissociation constant for AII was increased from 1.2 to 3.9 X 10(-9) M, whereas the total number of binding sites remained unchanged, suggesting a competitive nature of antagonism. A similar order of affinity or potency (saralasin much greater than EXP6803 greater than EXP6159 greater than EXP6155 greater than S8308) was observed in various in vitro and in vivo assays: rat smooth muscle cells AII binding, 45Ca++ influx in rat aortic rings, contractile response in isolated rabbit aorta and AII-induced pressor response in anesthetized rats. Responses (45Ca++ and contraction) elicited by norepinephrine or by KCl were unaltered by these agents at concentrations of up to 10(-4) M. In addition, they exerted no direct effect on the activity of rabbit angiotensin converting enzyme and rat renin. In conscious renal artery-ligated rats, EXP6155, EXP6159 and EXP6803 were p.o. inactive, but caused a rapid decrease in mean arterial pressure when administered i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 250, Issue 3, pp. 867-874, 09/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
Y. Du, J. Qiu, S. H. Nelson, and D. H. Wang
Regulation of type 1 ANG II receptor in vascular tissue: role of alpha 1-adrenoreceptor
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 1997; 273(4): R1224 - R1229.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
W. C. De Mello
Influence of Intracellular Renin on Heart Cell Communication
Hypertension, June 1, 1995; 25(6): 1172 - 1177.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1989 by the American Society for Pharmacology and Experimental Therapeutics.