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Polyethylene glycol derivative of enkephalin analogue

A technology of PEGylation and polyethylene glycol, applied in the field of medicine, can solve the problems of increasing the cost of synthesis and production, difficult control of reaction conditions, affecting the yield and purity of modified products, and achieving high yield and purity, and the reaction Conditional effects that are easy to control

Inactive Publication Date: 2011-11-23
HEBEI NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, the PEG modification scheme using the amino group of the enkephalin analog DPDPE as the modification site in the School of Pharmacy, University of Arizona still has disadvantages such as difficult control of the reaction conditions, affecting the yield and purity of the modified product, and increasing the synthesis (production) cost. factor

Method used

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  • Polyethylene glycol derivative of enkephalin analogue
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  • Polyethylene glycol derivative of enkephalin analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1 Preparation of precursor-C-terminal cysteine ​​MEK (MEK-Cys-NH 2 ) and C-terminal cysteine ​​DADAE (DADAE-Cys-NH 2 ):

[0074] The amino acids adopted include Fmoc-Tyr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-Met-OH, Fmoc-D-Ala-OH, Fmoc-Cys(Trt)-OH; wherein tBu is tert-butyl, and Trt is trityl. Synthesis of polypeptide sequences was performed manually. The solid-phase polypeptide synthesis glass reactor is custom-made, and the upper and lower chambers are separated by G2 filter plates, which are treated with silane reagents before use.

[0075] Steps:

[0076] 1. MEK-Cys-NH 2 and DADAE-Cys-NH 2 Synthesis:

[0077] (1) Rink Amide-AM resin, 0.160g (0.1mmol), swell in DMF for 10min, 20% piperidine / DMF1×10ml, remove Fmoc protection for 30min;

[0078] (2)CH 2 Cl 2 2×10ml, wash for 1min, including bottle cap;

[0079] (3) DMF1×10ml, wash for 1min;

[0080] (4)CH 3 OH1×10ml, wash for 1min;

[0081] (5) DMF1×10ml, wash for 1min;

[0082] (6)CH 3 OH1×10...

Embodiment 2

[0115] Example 2 Reacting enkephalin analogs with polyethylene glycol to synthesize PEGylated derivatives of enkephalin analogs:

[0116] Steps:

[0117] 1. mPEG 5000 -MAL generation

[0118] (1) Weigh mPEG 5000 -OH40.0g (8mmol), dissolved in 100ml CH 2 Cl 2 15ml of triethylamine and 19g of p-toluenesulfonyl chloride were added after stirring to dissolve, and the reaction was stirred at room temperature for about 6 hours. After the reaction was complete as detected by TLC, the solvent was removed by rotary evaporation, and 100ml of anhydrous ether was added to precipitate a solid to obtain mPEG 5000 -OTs.

[0119] (2) For the obtained mPEG 5000 -OTs were purified. Crude mPEG 5000 -OTs is dissolved in water, first use a separatory funnel to extract p-toluenesulfonyl chloride with ether, discard the ether layer, and then use CH 2 Cl 2 Extraction of mPEG in water 5000 -OTs, the aqueous layer was discarded, dried over anhydrous magnesium sulfate, and CH was removed by r...

Embodiment 3

[0134] Example 3 Pharmacodynamic experiment - detection of analgesic pharmacological activity of synthetic peptides:

[0135] In this example, the analgesic activity of four enkephalin analogues and polyethylene glycol modifications was determined, specifically including: MEK-Cys-NH 2 , DADAE-Cys-NH 2 , MEK-Cys (mPEG 5000 -MAL)-NH 2 , DADAE-Cys (mPEG 5000 -MAL)-NH 2 (Preparation of Example 1 and 2 of the present invention). When used, they were dissolved in normal saline according to the equimolar concentration of the control drug morphine, sterilized by filtration through a 0.45 μm filter membrane, and injected into the tail vein or lateral ventricle.

[0136] The control drug in this embodiment is morphine hydrochloride (Dexamethasone, Mor; produced by Northeast Sixth Pharmaceutical Factory, batch number: 001009, specification 10 mg / ml). When used, the clinical equivalent dose (10 mg / kg) converted from animal to human body weight is diluted with sterile normal saline, ...

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Abstract

The invention discloses polyethylene glycol derivatives of an enkephalin analogue, a preparation method, and a composition containing the same. The polyethylene glycol derivatives of an enkephalin analogue of the invention comprises an enkephalin analogue and polyethylene glycol covalently connected to a C end of the enkephalin analogue, wherein the enkephalin analogue has the following structure: X-Try-Y1-Gly-Phe-Y2-Y3-Z, and X is H or Ac; Y1 is D-Ala or Gly; Y2 is D-Ala or Met or Leu; Y3 is Cys or high Cys or Lys or Arg or His, and is a residue modified by PEG; Z is OH or NH2. The polyethylene glycol derivatives of the enkephalin analogue provided by the invention can be used to prepare analgesic drugs or precursor compounds of the drugs.

Description

technical field [0001] The invention relates to a pegylated derivative of an enkephalin analog, belonging to the technical field of medicine. Background technique [0002] Enkephalin (Enkephalin, ENK) is an endogenous analgesic substance discovered in the mid-1970s, including leucine enkephalin (Tyr-Gly-Gly-Phe-Leu, LEK) and methionine Two types of enkephalins (Tyr-Gly-Gly-Phe-Met, MEK) mainly act on δ-type opioid receptors. The analgesic activity is 2-3 times that of morphine, and the addictive effect is significantly weaker than that of morphine. The enkephalin peptide chain is short, the structure is simple, and the chemical synthesis is easy to realize. However, due to failure to solve the two major obstacles of its short half-life in vivo and difficulty in passing through the blood-brain barrier, it has not yet been developed into a drug. [0003] In the early 2000s, a research team at the University of Arizona had some encouraging results. They linked monosaccharide...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K17/08A61K38/33A61K47/48A61P29/00
Inventor 赵铁华文曙王良友
Owner HEBEI NORMAL UNIV
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