title: In vitro and in vivo studies with a series of hexapeptide endothelin antagonists.
abstract: The effects of different amino acids incorporated into the 16 and 17 positions of the C-terminal hexapeptide of ET-1 were examined. Structure-activity relationships (SAR) of the ET receptor antagonists PD 142893 [Ac-(D-Dip16-L-Leu17-L-Asp-L-Ile-L-Ile-L-Trp) (D-Dip = 3,3-D-diphenylalanine)] and PD 145065 [Ac-(D-Bhg16-L-Leu17-L-Asp-L-Ile-L-Ile-L-Trp) (D-Bhg = 5H-dibenzyl[a,d]cycloheptene-10,11-dihydro-glycine)] uncovered certain requirements for high potency. The disodium salt of PD 145065 has 4.0 and 15 nM binding affinity (IC50 values) for the ETA (rabbit renal artery vascular smooth-muscle cells) and ETB receptor (rat cerebellum), respectively. The compound is also an antagonist of ET-1- and SRTX-6c-stimulated vasoconstrictor activity, with pA2 values of 6.9 (rabbit femoral artery, ETA assay) and 7.1 (rabbit pulmonary artery, ETB assay). The tripeptidic ETA antagonist FR 139317 was found to be less active in the rabbit femoral artery, with a pA2 value of 6.0, and inactive in the rabbit pulmonary artery. Substitution of acidic and basic residues at position 17 in PD 142893 and PD 145065 indicates differences in selectivity. Incorporation of bulky non-natural amino acids at position 16 has led to potent nonselective analogues, including Ac-D-Bheg16-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp [D-Bheg (5H-dibenzo[a,d]cycloheptene glycine)]. The in vivo effects of single-bolus doses of selected ET antagonists on depressor and pressor responses to ET-1 in anesthetized ganglion-blocked rats were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, MI 48105.
authors.forename: A M
authors.initials: AM
authors.lastname: Doherty
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: X M
authors.initials: XM
authors.lastname: Cheng
authors.forename: K M
authors.initials: KM
authors.lastname: Welch
authors.forename: M A
authors.initials: MA
authors.lastname: Flynn
authors.forename: E E
authors.initials: EE
authors.lastname: Reynolds
authors.forename: D M
authors.initials: DM
authors.lastname: LaDouceur
authors.forename: L S
authors.initials: LS
authors.lastname: Davis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005730:Ganglionic Blockers / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D005730:Ganglionic Blockers; D007211:Indoles; D009842:Oligopeptides; D017466:Receptors, Endothelin; C079574:FR 139317; C076213:PD 142893; C082887:PD 145065; D016718:Arachidonic Acid