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非肽类缓激肽B2受体拮抗剂FR165649和激动剂FR190997的药理学特性

Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist, FR165649, and agonist, FR190997.

作者信息

Asano M, Hatori C, Sawai H, Johki S, Inamura N, Kayakiri H, Satoh S, Abe Y, Inoue T, Sawada Y, Mizutani T, Oku T, Nakahara K

机构信息

Department of Pharmacology, Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.

出版信息

Br J Pharmacol. 1998 Jun;124(3):441-6. doi: 10.1038/sj.bjp.0701813.

DOI:10.1038/sj.bjp.0701813
PMID:9647466
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565402/
Abstract
  1. The nonpeptide bradykinin (BK) B2 receptor antagonist, FR165649 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methylquinoline), and agonist, FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridyl methoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2-pyridylmethoxy group is the only structural difference between them. 2. Both FR165649 and FR190997 displaced [3H]-BK binding to B2 receptors in guinea-pig ileum membranes, with an IC50 of 4.7 x 10(-10) M and 1.5 x 10(-9) M, respectively. They also displaced [3H]-BK binding to B2 receptors in human lung fibroblast IMR-90 cells, with an IC50 of 1.6 x 10(-9) M and 9.8 x 10(-10) M, respectively. 3. In guinea-pig isolated ileum-preparations, FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration-response curves to BK on contraction. Analysis of the data produced a nominal pA2 value of 9.2+/-0.1 (n=5) and a slope of 1.4+/-0.1 (n=5). On the other hand, FR190997 induced concentration-dependent contraction of guinea-pig ilea with a pD2 of 7.9+/-0.2 and the contraction was inhibited by a specific peptide bradykinin B2 receptor antagonist, Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]BK) in a non-competitive manner. 4. In IMR-90 cells, FR165649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10(-7) M) of the concentration-response curves to BK on PI hydrolysis. FR190997 induced concentration-dependent PI hydrolysis in IMR-90 cells with a pD2 of 8.4+/-0.1, and this effect was inhibited by Hoe 140. 5. These results indicate that FR165649 and FR190997 are, respectively, a potent bradykinin B2 receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. FR165649 and FR190997 may be useful tools for studying the relationship between ligands and receptors.
摘要

  1. 非肽类缓激肽（BK）B2受体拮抗剂FR165649（8 - [2,6 - 二氯 - 3 - [N - [(E) - 4 - (N - 甲基氨基甲酰基)肉桂酰胺基乙酰基] - N - 甲基氨基]苄氧基] - 2 - 甲基喹啉）和激动剂FR190997（8 - [2,6 - 二氯 - 3 - [N - [(E) - 4 - (N - 甲基氨基甲酰基)肉桂酰胺基乙酰基] - N - 甲基氨基]苄氧基] - 2 - 甲基 - 4 - (2 - 吡啶甲氧基)喹啉）已被鉴定出来。这些化合物具有共同的化学结构，2 - 吡啶甲氧基是它们之间唯一的结构差异。

  2. FR165649和FR190997均可取代豚鼠回肠膜中[³H] - BK与B2受体的结合，IC50分别为4.7×10⁻¹⁰ M和1.5×10⁻⁹ M。它们还可取代人肺成纤维细胞IMR - 90中[³H] - BK与B2受体的结合，IC50分别为1.6×10⁻⁹ M和9.8×10⁻¹⁰ M。

  3. 在豚鼠离体回肠制备物中，FR165649对收缩无激动作用，且使收缩时BK的浓度 - 反应曲线平行右移。数据分析得出名义pA2值为9.2±0.1（n = 5），斜率为1.4±0.1（n = 5）。另一方面，FR190997诱导豚鼠回肠浓度依赖性收缩，pD2为7.9±0.2，且该收缩被特异性肽缓激肽B2受体拮抗剂Hoe 140（D - Arg - [Hyp3, Thi5, D - Tic7, Oic8]BK）以非竞争性方式抑制。

  4. 在IMR - 90细胞中，FR165649对磷脂酰肌醇（PI）水解无激动作用，且使PI水解时BK的浓度 - 反应曲线平行右移（在10⁻⁷ M时约为200倍的位移）。FR190997在IMR - 90细胞中诱导浓度依赖性PI水解，pD2为8.4±0.1，且该作用被Hoe 140抑制。

  5. 这些结果表明，FR165649和FR190997分别是强效的缓激肽B2受体拮抗剂和激动剂，且激动活性取决于非肽配体的一小部分。FR165649和FR190997可能是研究配体与受体之间关系的有用工具。

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