Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T
New Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4892-6. doi: 10.1073/pnas.91.11.4892.
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.
我们描述了一种强效且具选择性的内皮素（ET）B受体拮抗剂BQ-788 [N-顺式-2,6-二甲基哌啶甲酰基-L-γ-甲基亮氨酰-D-1-甲氧基羰基色氨酰-D-正亮氨酸]的特性。在体外，该化合物能强效且竞争性地抑制125I标记的内皮素1（ET-1）与人吉拉尔迪心脏细胞上的ETB受体结合（IC50为1.2 nM），但对其与人神经母细胞瘤细胞系SK-N-MC细胞上的ETA受体结合的抑制作用较弱（IC50为1300 nM）。在离体兔肺动脉中，BQ-788在浓度高达10 μM时未表现出激动剂活性，并能竞争性拮抗ETB选择性激动剂BQ-3020诱导的血管收缩（pA2为8.4）。在大鼠中，ETA选择性拮抗剂BQ-123（1 mg/kg，静脉注射）不影响对ET-1（0.3 nmol/kg，静脉注射）的短暂降压反应，但能强效抑制随后的持续升压反应；反之，BQ-788（1 mg/kg，静脉注射）可消除降压反应，导致快速出现明显增强的升压反应。因此，作为一种强效且具选择性的ETB受体拮抗剂，BQ-788可被视为研究ET在生理和病理过程中作用的有力工具。
