title: Pharmacological characterization of 3-azabicyclo[3,2,1] octane-1-yl-l-leucyl-d-tryptophanyl-d-4-Cl-phenylalanine: A novel ET(A) receptor-selective antagonist.
abstract: OBJECTIVE
  Pulmonary hypertension is a kind of disease associated with a very high rate of mortality. There are not many effective drugs for the treatment of pulmonary hypertension. Treatment with ET-1 receptor antagonists was proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin A receptor (ET(A)) antagonist for treatment of pulmonary hypertension, 242 peptide compounds were synthesized by structural optimization of a selective ET(A) receptor antagonist BQ-123. Among these, -azabicyclo[3,2,1]octane-1-yl-l-Leucyl-d-tryptophanyl-d-4-Cl-phenylalanine, named ETP-508, was selected for further harmacological characterization.
  
  
  METHODS
  Radioligand binding assay was performed to study the binding affinity of ETP-508 for ET(A) and ET(B) receptors. The biological activity of ETP-508 was evaluated in isolated rat aortic ring experiment and in systemic arterial pressure experiment. In addition, hypotensive effect of ETP-508 was investigated on hypoxia-induced pulmonary hypertension.
  
  
  RESULTS
  ETP-508 binds to endothelin ET(A) receptor with >10,000-fold higher affinity than to endothelin B receptor in rat lung tissue preparation. ETP-508 inhibited endothelin-1 (ET-1)-induced contraction of isolated rat aortic ring and shifted the cumulative concentration-contraction response curve to ET-1 to right with no change in the maximal response. In vivo, ETP-508 inhibited the increased effect of ET-1 on mean systemic arterial pressure. Pre-treatment with ETP-508 by intravenous infusion significantly inhibited chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. ETP-508 also significantly inhibited the increase in lung ET-1 expression level, hemoglobin, red-cell count and red-cell hematocrit as induced by hypoxia. Furthermore, ETP-508 partially reversed pre-established pulmonary hypertension and right ventricle hypertrophy by chronic hypoxia.
  
  
  CONCLUSIONS
  These results indicated that ETP-508 is a novel highly selective ET(A) receptor antagonist and may have a great potential to be developed as a drug of anti-pulmonary hypertension.
authors.affiliation: Department of Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Ke-Liang
authors.initials: KL
authors.lastname: Liu
authors.forename: Jian-Quan
authors.initials: JQ
authors.lastname: Zheng
authors.forename: Mu-Gen
authors.initials: MG
authors.lastname: Chi
authors.forename: Jun-Jun
authors.initials: JJ
authors.lastname: Dong
authors.forename: Si-Jian
authors.initials: SJ
authors.lastname: Dong
authors.forename: Ze-Hui
authors.initials: ZH
authors.lastname: Gong
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000737:chemistry / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C535090:3-azabicyclo(3.2.1)octan-1-yl-leucyl-tryptophyl-4-chlorophenylalanine; D053961:Azabicyclo Compounds; D001381:Azepines; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; C083116:BQ 485; C072247:cyclo(Trp-Asp-Pro-Val-Leu)