title: Structure-activity relationships of the potent combined endothelin-A/endothelin-B receptor antagonist Ac-DDip16-Leu-Asp-Ile-Ile-Trp21: development of endothelin-B receptor selective antagonists.
abstract: The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His16-Leu17-Asp18-Ile19-Ile20-Trp21) to the development of potent antagonists at both receptor subtypes (ETA and ETB). In particular, it has been shown that Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ETB receptor selective ligands and the pharmacological differences that exist between species ETB receptors with respect to their affinity for C-terminal hexapeptide antagonists.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Cody
authors.forename: J X
authors.initials: JX
authors.lastname: He
authors.forename: P L
authors.initials: PL
authors.lastname: DePue
authors.forename: L A
authors.initials: LA
authors.lastname: Waite
authors.forename: D M
authors.initials: DM
authors.lastname: Leonard
authors.forename: A M
authors.initials: AM
authors.lastname: Sefler
authors.forename: J S
authors.initials: JS
authors.lastname: Kaltenbronn
authors.forename: S J
authors.initials: SJ
authors.lastname: Haleen
authors.forename: D M
authors.initials: DM
authors.lastname: Walker
authors.forename: M A
authors.initials: MA
authors.lastname: Flynn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010455:Peptides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C076213:PD 142893