title: Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788.
abstract: We describe the characteristics of a potent and selective endothelin (ET) B-receptor antagonist, BQ-788 [N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D -1- methoxycarbonyltryptophanyl-D-norleucine]. In vitro, this compound potently and competitively inhibits 125I-labeled endothelin 1 (ET-1) binding to ETB receptors on human Girardi heart cells (IC50, 1.2 nM) but only poorly inhibits the binding to ETA receptors on human neuroblastoma cell line SK-N-MC cells (IC50, 1300 nM). In isolated rabbit pulmonary arteries, BQ-788 shows no agonist activity up to 10 microM and competitively antagonizes the vasoconstriction induced by an ETB-selective agonist, BQ-3020 (pA2, 8.4). In rat, an ETA-selective antagonist, BQ-123 (1 mg/kg, i.v.), does not affect transient depressor response to ET-1 (0.3 nmol/kg, i.v.) but potently inhibits following sustained pressor response; vice versa, BQ-788 (1 mg/kg, i.v.) abolishes the depressor response, resulting in a rapid onset of apparently enhanced pressor response. Thus, being a potent and selective ETB receptor antagonist, BQ-788 may be considered as a powerful tool for investigating the role of ET in physiological and pathological processes.
authors.affiliation: New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishikawa
authors.forename: M
authors.initials: M
authors.lastname: Ihara
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: T
authors.initials: T
authors.lastname: Mase
authors.forename: N
authors.initials: N
authors.lastname: Mino
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: T
authors.initials: T
authors.lastname: Fukuroda
authors.forename: T
authors.initials: T
authors.lastname: Fukami
authors.forename: S
authors.initials: S
authors.lastname: Ozaki
authors.forename: T
authors.initials: T
authors.lastname: Nagase
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D065128:Endothelin Receptor Antagonists; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D014407:Tumor Cells, Cultured
chemical_list: D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; C086539:BQ 788