title: Structure-activity relationships of C-terminal endothelin hexapeptide antagonists.
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.
authors.affiliation: Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
authors.forename: W L
authors.initials: WL
authors.lastname: Cody
authors.forename: P L
authors.initials: PL
authors.lastname: DePue
authors.forename: J X
authors.initials: JX
authors.lastname: He
authors.forename: L A
authors.initials: LA
authors.lastname: Waite
authors.forename: D M
authors.initials: DM
authors.lastname: Leonard
authors.forename: N L
authors.initials: NL
authors.lastname: Leitz
authors.forename: D T
authors.initials: DT
authors.lastname: Dudley
authors.forename: S T
authors.initials: ST
authors.lastname: Rapundalo
authors.forename: G P
authors.initials: GP
authors.lastname: Hingorani
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000737:chemistry* / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007295:Inositol Phosphates; D009842:Oligopeptides; D017466:Receptors, Endothelin; D016718:Arachidonic Acid