Document Detail

Dipeptide sulfonamides as endothelin ETA/ETB receptor antagonists.
MedLine Citation:
PMID:  12056554     Owner:  NLM     Status:  MEDLINE    
Endothelin-1 (ET-1) is a potent mitogen and modulator of vascular tone. It is synthesized and released from endothelial cells and acts upon two receptor subtypes designated as ETA and ETB. In this study, a series of potent dipeptide sulfonamide dual-endothelin ETA/ETB receptor antagonists were prepared to investigate their potential benefit in vascular diseases. CGS 31398 inhibited [125I]ET-1 binding to human ETA and ETB receptors expressed in Chinese hamster ovary (CHO) cells (ETA/CHO, ETB/CHO) with respective IC50 values of 0.26 and 0.12 nM. However, in anesthetized rats, this compound markedly potentiated ET-1-induced renal vascular resistance, a response normally observed with selective ETB receptor antagonists. To determine whether species differences account for these results, a direct comparison was made between binding to rat and rabbit aortic membranes versus functional antagonism in isolated rat aortic rings. It was found that CGS 31398 had potent affinity for the ETA receptor in rat and rabbit aorta with IC50 values of 0.87 and 0.79 nM, respectively. Inhibition of ET-1-induced contractions of rat aorta by the compound was considerably weaker than expected (pKB = 6.4), while that of sarafotoxin S6c induced contraction of dog saphenous vein (100% inhibition at 100 nM) was consistent with corresponding binding data. These results suggest that although CGS 31398 is a potent dual inhibitor of ETA/ETB receptor binding, it surprisingly displays potent ETB and weak ETA receptor antagonism in functional assays.
Gary M Ksander; Suraj S Shetty; Dominick DelGrande; Joseph L Balwierczak; Charles W Bruseo; Paula Savage; Reynalda deJesus; Andrew Yuan; Randy L Webb; Arco Y Jeng
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Canadian journal of physiology and pharmacology     Volume:  80     ISSN:  0008-4212     ISO Abbreviation:  Can. J. Physiol. Pharmacol.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-06-11     Completed Date:  2002-12-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372712     Medline TA:  Can J Physiol Pharmacol     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  464-9     Citation Subset:  IM    
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, Summit, NJ 07901, USA.
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MeSH Terms
Aorta, Thoracic / drug effects,  metabolism
CHO Cells
Dipeptides / chemistry,  metabolism,  pharmacology*
Dose-Response Relationship, Drug
Organ Culture Techniques
Rats, Sprague-Dawley
Receptor, Endothelin A
Receptor, Endothelin B
Receptors, Endothelin / antagonists & inhibitors*,  metabolism
Sulfonamides / chemistry,  metabolism,  pharmacology*
Vasoconstriction / drug effects,  physiology
Reg. No./Substance:
0/Dipeptides; 0/Receptor, Endothelin A; 0/Receptor, Endothelin B; 0/Receptors, Endothelin; 0/Sulfonamides

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