Development of selective agonists and antagonists of the endothelin receptors

内皮素受体选择性激动剂和拮抗剂的开发

• 批准号: 06556050
• 负责人: KARAKI Hideaki
• 金额: $ 10.05万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06556050/
• 关键词: Endothelin; Endothelin receptor; Endothelin receptor antagonists; IRL 1620; RES-701-1; 血管; 内皮細胞; 気管; 血管平滑筋; 血管内皮; 消化管平滑筋

Endothelin (ET) is a potent vasoconstrictor peptide derived from vascular endothelium and other tissues. There are two types of ET receptors, the ETA and the ETB receptors. Because ET has various effects on isolated tissues at very low concentrations, and many tissues produce ET,it is expected that ET has variety of effects in out body. However, physiological and pathophysiological roles of ET have not been identified mainly because we do not have selective agonists and antagonists of these ET reseptors. The major purpose of our project was to find out such agonists and antagonists. We found that a selective agonist of the ETB receptor, IRL 1620, from the C-terminal peptides of ET-1. IRL 1620 is more selective than other ETB agonists and is more easily labeled by I125. We also found a selective ETB antagonist, RES-701-1 from bacterial products. This antagonist showed different characteristics from other ETB antagonist, BQ788, indicating the presence of the ETB receptor subtypes.

内皮素（ET）是一种有效的血管收缩肽，来源于血管内皮和其他组织。有两种类型的ET受体，ETA和ETB受体。由于ET在极低浓度下对离体组织有多种作用，且许多组织产生ET，因此预计ET在体外有多种作用。然而，ET的生理和病理生理作用尚未确定，主要是因为我们没有这些ET受体的选择性激动剂和拮抗剂。我们项目的主要目的是找出这些激动剂和拮抗剂。我们从ET-1的c端肽中发现了一种选择性的ETB受体激动剂IRL 1620。IRL 1620比其他ETB激动剂更具选择性，更容易被I125标记。我们还从细菌产物中发现了一种选择性ETB拮抗剂RES-701-1。该拮抗剂表现出与其他ETB拮抗剂BQ788不同的特征，表明存在ETB受体亚型。

项目成果

Sudjarwo et al.: "Coupling of the endothelin ET_A and ET_B receptors to Ca mobilization and Ca sensitization in vasalar smouth muscle" European Journal of Pharmacology. 289. 197-204 (1995)

Sudjarwo 等人：“血管口肌中内皮素 ET_A 和 ET_B 受体与 Ca 动员和 Ca 敏化的耦合”欧洲药理学杂志。

KARAKI,H.et al.: "Novel antagonist of endoghelin ETB1 and ETB2 receptors,BQ-788;effects on blood vessels and small intestine." Biochem.Biophys.Res.Commun.205. 168-173 (1994)

KARAKI,H.等人：“内皮素 ETB1 和 ETB2 受体的新型拮抗剂，BQ-788；对血管和小肠的影响。”

KARAKI,H.AND MATSUDA,Y.: "RES-701-1 : a novel endothelin ET_B receptor antagonist" Cardiovasc. Drug Rev.14. 17-35 (1996)

KARAKI,H. 和 MATSUDA,Y.：“RES-701-1：一种新型内皮素 ET_B 受体拮抗剂”Cardiovasc。

SUDJARWO,S.A., HORI,M., TANAKA,T., MATSUDA,Y., OKADA,T.AND KARAKI,H.: "Subtypes of Endothelin ET_A and ET_B receptors mediating venous smooth muscle contraction" Biochem. Biophys. Res. Commun.200. 627-633 (1994)

SUDJARWO,S.A.、HORI,M.、TANAKA,T.、MATSUDA,Y.、OKADA,T. 和 KARAKI,H.：“介导静脉平滑肌收缩的内皮素 ET_A 和 ET_B 受体亚型”Biochem。

Kunieda et al: "A mutation in endothelin-B receptor gene causes myenteric aganglionosis and coat color spotting in rat." DNA Res.3. 101-105 (1996)

Kunieda 等人：“内皮素 B 受体基因的突变会导致大鼠出现肌间神经节缺失和毛色斑点。”