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C-terminal aromatic ester modified endomorphin-1 analogue as well as synthetic method and application thereof

A technology of endomorphin and synthesis method, applied in the field of endomorphin-1 analogs and its synthesis, can solve the problem of endomorphin-1 with short analgesic time, poor analgesic effect, analgesic tolerance, cardiovascular and respiratory Systemic side effects and other problems, to achieve the effect of improving enzymatic stability, improving fat solubility, improving utilization rate and analgesic efficacy

Active Publication Date: 2018-06-01
黑龙江省工研院资产经营管理有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The present invention aims to solve the problems of short analgesic time, enzymatic stability, poor analgesic effect of peripheral administration, analgesic tolerance, cardiovascular and respiratory system side effects of existing endomorphin-1, and provides C - Endomorphin-1 analogs modified by aromatic esterification at the terminal and their synthesis and application

Method used

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  • C-terminal aromatic ester modified endomorphin-1 analogue as well as synthetic method and application thereof
  • C-terminal aromatic ester modified endomorphin-1 analogue as well as synthetic method and application thereof
  • C-terminal aromatic ester modified endomorphin-1 analogue as well as synthetic method and application thereof

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specific Embodiment approach 1

[0040] Specific embodiment 1: The structure of the endomorphin-1 analog modified by aromatic esterification at the C-terminal of this embodiment is as follows:

[0041]

[0042] where n=1, 2 or 3.

specific Embodiment approach 2

[0043] Specific embodiment 2: The synthesis method of endomorphin-1 analogs modified by C-terminal aromatic esterification in this embodiment includes the following steps:

[0044] 1. Synthesis of benzyloxycarbonyl-tryptophan benzyl ester / phenethyl ester / phenyl propyl ester

[0045] Add benzyloxycarbonyl-tryptophan and 4-dimethylaminopyridine to the redistilled dichloromethane reaction solution, then add aromatic alcohol, and ice-bath at 0-5°C for 5-10 minutes to obtain a reaction mixture; wherein benzyloxycarbonyl -The molar ratio of tryptophan and 4-dimethylaminopyridine is 1:(0.3~0.5), and the volume ratio of benzyloxycarbonyl-tryptophan and aromatic alcohol is 1mol:(1~4)mL; The aromatic alcohol is benzyl alcohol, phenylethyl alcohol or phenylpropanol;

[0046] Dissolve N,N'-dicyclohexylcarbodiimide in redistilled dichloromethane solution, add it to the reaction mixture, stir and react at 0-5°C for 20-40min, then react at room temperature for 10-15h; The molar ratio of ox...

specific Embodiment approach 3

[0060] Specific embodiment three: this embodiment differs from specific embodiment two in that: the specific method of washing in step one is: washing with 5% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution successively. Others are the same as in the second embodiment.

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Abstract

The invention discloses a C-terminal aromatic ester modified endomorphin-1 analogue as well as a synthetic method and application thereof, relates to an endomorphin-1 analogue as well as synthesis andapplication thereof, and aims to solve the problems of short analgesia time, low enzymolysis stability, poor analgesic effect of peripheral administration, analgesia tolerance and side effects on a cardiovascular system and a respiratory system in the conventional endomorphin-1. The analogue is a C-terminal aromatic ester modified endomorphin-1 analogue. The method comprises the following steps:I, synthesis of benzyloxycarbonyl-tryptophan benzyl / phenylethyl / phenylpropyl; II, synthesis of benzyloxycarbonyl-tyrosine-proline; III, synthesis of carbobenzoxy-tyrosine-proline-tryptophan benzyl / phenylethyl / phenylpropyl; IV, synthesis of tyrosine-proline-tryptophan benzyl / phenethyl / phenylpropyl. The C-terminal aromatic ester modified endomorphin-1 analogue is applied to the preparation of a polypeptide analgesic medicament.

Description

technical field [0001] The present invention relates to an endomorphin-1 analogue and its synthesis method and application. Background technique [0002] Opioids and opioid drugs act on opioid receptors on cell membranes and are widely used for pain relief. At present, it is believed that there are at least three subtypes in the nervous system, namely μ-, δ- and κ-opioid receptors, and the main action of opioids such as morphine is realized through the μ-opioid receptors located in the central nervous system. Therefore, the research on endogenous ligands of μ-opioid receptors is of great significance. As early as 1997, Zadina and colleagues discovered the endogenous μ-opioid receptor ligand, endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 , EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ,EM-2). Among all known opioids, endomorphins have extremely high affinity and selectivity for μ-opioid receptors. Endomorphins participate in the regulation of many functions such as pain perception...

Claims

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Application Information

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IPC IPC(8): C07K14/665C07K1/107C07K1/02A61K47/54A61K38/06A61P29/00
CPCA61K38/00C07K14/665C07K19/00
Inventor 王长林杨代军袁碧玉
Owner 黑龙江省工研院资产经营管理有限公司
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