Development of a New Analgesic Based on Metabolism of Endomorphin, an Endogenous Opioid Peptide

基于内吗啡(一种内源性阿片肽)代谢的新型镇痛药的开发

基本信息

项目摘要

Endomorphin-2 (Tyr-Pro-Phe-PheNH_2) was discovered as an endogenous ligand for the mu-opioid receptor. The physiological function of endomorphin-2 as a neurotransmitter or neuromodulator may cease through the rapid enzymatic process in the synapse of brain, as for other neuropeptides. The present study was conducted to examine the metabolism of endomorphin-2 by synaptic membranes prepared from mouse brain. Major metabolites were free tyrosine, free phenylalanine, Tyr-Pro and PheNH_2. Both the degradation of endomorphin-2 and the accumulation of major metabolites were inhibited by specific inhibitors of dipeptidyl peptidase IV, such as diprotin A and B. On the other hand, the accumulation of Phe-PheNH_2 and Pro-Phe-PheNH_2 was increased in the presence of bestatin, an aminopeptidase inhibitor, whereas that of free phenylalanine and PheNH_2 was decreased. Furthermore, purified dipeptidyl peptidase IV hydrolyzed endomorphin-2 at the cleavage site, Pro^2-Phe^3 bond. Thus, degradation of endomorphin-2 by brain synaptic membranes seems to take place mainly through the cleavage of Pro^2-Phe^3 bond by dipeptidyl peptidase IV, followed by release of free phenylalanine and Phe NH_2 from the liberated fragment, Phe-Phe NH_2 by aminopeptidase. We have also examined that the effect of diprotin A on the antinociception induced by intracerebroventricularly administered endomorphin-2 in the mouse paw withdrawal test. Diprotin A simultaneously injected with endomorphin-2 enhanced endomorphin-2-induced antinociception. These results indicate that dipeptidyl peptidase IV may be an important peptidase responsible for terminating endomorphin-2-induced antinociception at the supraspinal level in mice. These findings also suggest that selective dipeptidyl peptidase IV inhibitors or dipeptidyl peptidaseIV-resistant endomorphin-2 analogues have the potential for the clinical use as analgesics.
内吗啡肽-2(Tyr-Pro-Phe-PheNH_2)是μ-阿片受体的内源性配体。内吗啡肽-2作为神经递质或神经调质的生理功能可能与其他神经肽一样,通过脑突触中的快速酶促过程而终止。本研究旨在研究内吗啡肽-2在小鼠脑突触膜上的代谢。主要代谢产物为游离酪氨酸、游离苯丙氨酸、Tyr-Pro和PheNH_2。内吗啡肽-2的降解和主要代谢产物的积累都被二肽基肽酶IV的特异性抑制剂如diprotin A和B抑制。而苯丙氨酸和苯丙氨酸氨解氨酶抑制剂bestatin的存在则使Phe-PheNH_2和Pro-Phe-PheNH_2的积累增加,而使游离苯丙氨酸和PheNH_2的积累减少。此外,纯化的二肽基肽酶IV在切割位点Pro^2-Phe^3键处水解内吗啡肽-2。因此,脑突触膜对内吗啡肽-2的降解似乎主要是通过二肽基肽酶IV切割Pro^2-Phe^3键,然后通过氨肽酶从释放的片段Phe-Phe NH_2中释放游离苯丙氨酸和Phe NH_2来进行的。我们还在小鼠缩爪实验中检测了双蛋白A对侧脑室注射内吗啡肽-2诱导的抗伤害性感受的作用。同时注射内吗啡肽-2可增强内吗啡肽-2诱导的抗伤害作用。这些结果表明,二肽基肽酶IV可能是一个重要的肽酶负责终止内吗啡肽-2诱导的抗伤害性在脊髓上水平的小鼠。这些发现也表明,选择性二肽基肽酶IV抑制剂或二肽基肽酶IV抗性内吗啡肽-2类似物具有作为镇痛剂的临床应用的潜力。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV : an in vitro and in vivo study
二肽基肽酶 IV 启动小鼠脊髓上水平内吗啡-2 的降解:一项体外和体内研究
  • DOI:
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Suganuma;M. et al.;Satoshi Akiba;Nobuaki Mizutani;Chikai Sakurada 他5名
  • 通讯作者:
    Chikai Sakurada 他5名
Development of a new analgesic based on metabolism of endomorphin, an endogenous opioid peptide
开发基于内吗啡(一种内源性阿片肽)代谢的新型镇痛药
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    J.Mori;T.Hayashi;M.Iwashima;T.Matsunaga;H.Saito;Chikai Sakurada
  • 通讯作者:
    Chikai Sakurada
Chikai Sakurada 他: "Degradation of endomorphin-2 at the supraspinal level in mice is initiated by dipeptidyl peptidase IV : an in vitro and in vivo study"Biochemical Pharmacology. 66. 653-661 (2003)
Chikai Sakurada 等人:“二肽基肽酶 IV 引发小鼠脊髓上水平的内啡肽-2 降解:一项体外和体内研究”《生化药理学》66. 653-661 (2003)。
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SAKURADA Chikai其他文献

SAKURADA Chikai的其他文献

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{{ truncateString('SAKURADA Chikai', 18)}}的其他基金

Development of anti-dementia drugs based on metabolism of nociceptin by synaptic membranes of hippocampus.
基于海马突触膜代谢伤害感受素开发抗痴呆药物。
  • 批准号:
    18590068
  • 财政年份:
    2006
  • 资助金额:
    $ 2.3万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)

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二肽基肽酶-IV 在先天免疫反应中的作用
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P4-ROLE OF DIPEPTIDYL PEPTIDASE IV IN PERIPHERAL NEUROGENESIS AND NEUROBLASTOMAS
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神经肽 Y 和二肽基肽酶 IV (CD26) 在慢性疲劳综合征中的作用
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Neuropeptide Y and dipeptidyl-peptidase IV (CD26) in chronic fatigue syndrome
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