Approach of a new pain-regulated substance spinophrin from bovine spinal cord and its application

一种新的牛脊髓疼痛调节物质spinophrin的研究及其应用

• 批准号: 13671627
• 负责人: HAZATO Tadahiko
• 金额: $ 2.18万
• 依托单位: THE TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671627/
• 关键词: Spinorphin; Enkephalin; Spinal Cord; Pain; Opioid; DPPIII; オピオイド; enkephain

We found a novel endogenous inhibitor that modulated enkephalin activity and purified it from spinal cord based on its inhibitory activity toward enkephalin-degrading enzymes. Structural analysis revealed the factor to be L-V-V-Y-P-W-T and it was named spinophrin. It inhibits dipeptidyl peptidaseIII(EC3.4.14.4:DPPIII) as well as aminopeptidase(EC3.4.1:AP), neutral endopeptidase(EC3.4.24.11: NEP), angiotensin-converting enzyme (EC3.4.15.1:ACE) from monkey brain, especially to DPPIII(Ki: 5.1x10-7). Spinorphin also inhibited polymorphonuclear neutrophil(PMN) function by suppressing FMLP binding to its receptor on PMNs. Recently we reported that this inhibitor against DPP111 significantly inhibited bradykinin-induced responses. It showed analgesia in a different manner compared with morphine. Its analgesia may be caused by an inhibitory activity toward enkephalin-degrading enzyme, DPPIII. It would be interesting to determine whether spinorphin or more active related compounds inhibit neuropathic pain, known to be insensitive to morphine. Spinorphin plays important roles in pain and further search of its analogues may lead to finding of a novel type of drugs which will be useful for various clinical application

我们发现了一种新的内源性调节脑啡肽活性的抑制剂，并根据其对脑啡肽降解酶的抑制活性从脊髓中纯化出来。结构分析表明该因子为L-V-V-Y-P-W-T，命名为spinophrin。抑制猴脑二肽基肽酶ⅱⅱ（EC3.4.14.4:DPPIII）、氨基肽酶（EC3.4.1:AP）、中性内肽酶（EC3.4.24.11: NEP）、血管紧张素转换酶（EC3.4.15.1:ACE），尤其对DPPIII（Ki: 5.1 × 10-7）具有抑制作用。Spinorphin还通过抑制FMLP与其受体在PMN上的结合来抑制多形核中性粒细胞（PMN）的功能。最近我们报道了这种抗DPP111的抑制剂能显著抑制缓激肽诱导的反应。其镇痛效果与吗啡不同。其镇痛作用可能与对脑啡肽降解酶DPPIII的抑制作用有关。确定spinorphin或更活跃的相关化合物是否能抑制神经性疼痛（已知对吗啡不敏感）将是一件有趣的事情。Spinorphin在疼痛中起着重要的作用，对其类似物的进一步研究可能会发现一种新的药物，这将有助于各种临床应用

项目成果

佐藤 洋: "脳脊髄液中におけるエンケファリン代謝酵素dipeptidyl peptidase(DPPIII)の動態"麻酔. (印刷中).

Hiroshi Sato：“脑脊液中脑啡肽代谢酶二肽基肽酶 (DPPIII) 的动力学”麻醉（正在出版）。

Honda, M: "Spinorphin, an endogenous inhibitor of enkephalin-degrading enzymes, potentiates leu-enkephalin-induced anti-allodynic and anti-nociceptive effects in mice"Jpn. J. Pharmacol.. 87. 261-267 (2001)

Honda, M：“Spinorphin 是一种脑啡肽降解酶的内源性抑制剂，可增强亮氨酸脑啡肽诱导的小鼠抗异常疼痛和抗伤害性作用”Jpn。

Yamamoto Y: "Spinorphin as an Endogenous Inhibitor of Enkephalin-degrading Enzyame Roles"Current Protein and Peptide Sciences. 3. 587-599 (2002)

Yamamoto Y：“旋转啡肽作为脑啡肽降解酶作用的内源性抑制剂”当前蛋白质和肽科学。

Shimamura M: "A hypoxia-dependent nitroimidazole KIN-841 inhibits angiogenesis by blocking production of angiogenic factor"Brit. J. Cancer. (In press).

Shimamura M：“缺氧依赖性硝基咪唑 KIN-841 通过阻断血管生成因子的产生来抑制血管生成”Brit。

Shimamura M: "A hypoxia-dependent nitromidazole KIN-841 inhibits angiogenesis by blocking production of angiogenic factor"Brit.J.Caner. (in press).

Shimamura M：“缺氧依赖性硝基咪唑 KIN-841 通过阻断血管生成因子的产生来抑制血管生成”Brit.J.Caner。