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Non-natural amino acid modified endomorphin-1 analogue as well as synthesis method and application thereof

An unnatural amino acid, endomorphin technology, applied in the field of biomedicine, can solve the problems of easy enzymolysis and short action time, and achieve the effect of prolonging the effect, improving the affinity and the stability of enzymolysis

Inactive Publication Date: 2015-09-02
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of endomorphins is still subject to many limitations, such as its short action time, easy to be enzymatically hydrolyzed in the body, and difficult to penetrate the blood-brain barrier to reach the central nervous system, etc.

Method used

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  • Non-natural amino acid modified endomorphin-1 analogue as well as synthesis method and application thereof
  • Non-natural amino acid modified endomorphin-1 analogue as well as synthesis method and application thereof
  • Non-natural amino acid modified endomorphin-1 analogue as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: Synthesis of [(2-thienyl)Map4]EM-1:

[0071] (1) Amide synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(2-thiophene)propionic acid

[0072] Dissolve N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(2-thiophene)propionic acid in anhydrous dichloromethane, and add N-tert-butoxy Carbonyl-3-amino-2-methenyl-3-(2-thiophene)propionic acid 4~5 times the amount of N,N-diisopropylethylamine, 1.45~1.5 times the amount of 1-hydroxyl Benzotriazole, 1.5~1.6 times the amount of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stir and dissolve fully, add N-tert-butoxycarbonyl-3-amino-2- Ammonia water with 1.2 to 1.5 times the molar weight of methenyl-3-(2-thiophene)propionic acid was reacted at room temperature for 10 to 12 hours; after the reaction was completed, it was washed, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a white solid N-tert Amide of butoxycarbonyl-3-amino-2-methenyl-3-(2-thiophene)propionic acid.

[0073] (2) ...

Embodiment 2

[0087] Embodiment 2: Synthesis of [(3-thienyl)Map4]EM-1:

[0088] (1) Amide synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(3-thiophene)propionic acid

[0089] Dissolve N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(3-thiophene)propionic acid in anhydrous dichloromethane, add N-tert-butoxy Carbonyl-3-amino-2-methenyl-3-(3-thiophene)propionic acid 4~5 times the amount of N,N-diisopropylethylamine, 1.45~1.5 times the amount of 1-hydroxyl Benzotriazole, 1.5~1.6 times the amount of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stir and dissolve fully, add N-tert-butoxycarbonyl-3-amino-2- Ammonia water with 1.2 to 1.5 times the molar weight of methenyl-3-(3-thiophene)propionic acid was reacted at room temperature for 10 to 12 hours; after the reaction was completed, it was washed, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a white solid N-tert Amide of butoxycarbonyl-3-amino-2-methenyl-3-(3-thiophene)propionic acid;

[0090] (2) S...

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Abstract

The invention discloses a non-natural amino acid modified endomorphin-1 analogue. A synthesis method comprises the following step: replacing amino acid phenylalanine at a fourth site from a terminal N to a terminal C of parent endomorphin-1 by respectively using 2-thienyl substituted alpha-alkenyl-beta-amino acid and 3-thienyl substituted alpha-alkenyl-beta-amino acid. The affinity and enzymatic hydrolysis stability of a mu opioid receptor of the non-natural amino acid modified endomorphin-1 analogue can be effectively improved, and thus the in-vivo analgesic effect of the non-natural amino acid modified endomorphin-1 analogue can be further improved and prolonged; and the non-natural amino acid modified endomorphin-1 analogue is subjected to pharmacological activity identification by virtue of radioligand receptor binding experiments, in-vitro organ biological assays and in-vitro enzymatic hydrolysis stability and warm bath tail-flick analgesic experiments, and results show that compared with parent endomorphin-1, the synthesized non-natural amino acid modified endomorphin-1 analogue disclosed by the invention has higher affinity, higher enzymatic hydrolysis stability and higher analgesic activity, and has potential application values of being taken as clinical polypeptide analgesic medicines.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of endomorphin-1 analogues, in particular to a class of unnatural amino acid modified endomorphin-1 analogues and a synthesis method thereof. The invention also relates to the endomorphin-1 analogues The application of drugs in the regulation of analgesia. Background technique [0002] Pain is one of the most common reasons patients seek medical care, and it imposes a huge economic burden on patients, families, society, government and industry. At present, about 20% of people in the world suffer from pain, and opioids are the first choice for the treatment of severe acute pain, postoperative pain and cancer pain. At present, there is no other analgesic that can replace opioids in severe cases. Therapeutic status in pain. Opioid peptide is an endogenous neurotransmitter that plays an analgesic effect through opioid receptors. Once discovered, opioid peptide has attracted w...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/023A61K38/07A61P25/04
Inventor 王锐刘鑫王媛王丹
Owner LANZHOU UNIVERSITY
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