title: Structure-activity studies of endothelin leading to novel peptide ETA antagonists.
abstract: With the goal of producing receptor antagonists, numerous monocyclic and bicyclic endothelin analogs were prepared and tested for vasoconstrictor activity, receptor affinity and functional antagonist activity. Bis-penicillamine endothelin analogs containing Ala or Asn at position 18 were functional antagonists, with Ki values of 20-40 nM but KB values of about 1 microM (e.g., [Pen1,11, Nle7, Ala18]-endothelin-1, Ki = 42 nM, KB = 1.2 microM). While these peptides are antagonists at the ETA receptor, they appear to be at least partial agonists at another receptor subtype.
authors.affiliation: Department of Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.
authors.forename: J T
authors.initials: JT
authors.lastname: Hunt
authors.forename: V G
authors.initials: VG
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: McMullen
authors.forename: E C
authors.initials: EC
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Bolgar
authors.forename: C L
authors.initials: CL
authors.lastname: Delaney
authors.forename: S M
authors.initials: SM
authors.lastname: Festin
authors.forename: D M
authors.initials: DM
authors.lastname: Floyd
authors.forename: A
authors.initials: A
authors.lastname: Hedberg
authors.forename: S
authors.initials: S
authors.lastname: Natarajan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002339:Carotid Arteries; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C089337:endothelin-1, Pen(1,11)-Nle(7)-Ala(18)-; C089336:endothelin-1, Pen(1,11)-Nle(7)-Asn(18)-