Abstract:
:The discovery of selective endothelin (ET) receptor antagonists will facilitate identification of the physiological and pathological roles for ET and its isopeptides. Structure-activity studies of the C-terminal hexapeptide of ET have been carried out to elucidate those amino acids important for receptor binding and agonist or antagonist activity. Binding studies were performed in rat heart ventricle, rabbit renal artery vascular smooth muscle cells, and rat cerebellum. In addition, many of the compounds have been evaluated functionally for their effects on endothelin-1-induced arachidonic acid release and inositol phosphate accumulation in specific cell lines. Selected compounds have been evaluated in a functional bioassay in tissue preparations specifically expressing either ETA or ETB receptors. We have previously described the structure-activity relationships in the hydrophobic C-terminal hexapeptide of ET, a region known to be highly important for receptor recognition. A mono-D-amino acid scan of the ET[16-21] revealed that substitution at His gave rise to analogs with significantly enhanced binding affinity. We have further evaluated the C-terminal region and will describe the design, synthesis, and pharmacological evaluation of several novel and potent ET peptide receptor antagonists.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Doherty AM,Cody WL,DePue PL,He JX,Waite LA,Leonard DM,Leitz NL,Dudley DT,Rapundalo ST,Hingorani GPdoi
10.1021/jm00070a001subject
Has Abstract,Author List Incompletepub_date
1993-09-03 00:00:00pages
2585-94issue
18eissn
0022-2623issn
1520-4804journal_volume
36pub_type
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