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Coupling oligoarginine and 2 site substituted endomorphin-1 analogue as well as synthetic method and application thereof

A technology of oligoarginine and endomorphin, which is applied to the preparation method of peptides, drug combinations, chemical instruments and methods, etc., to achieve good stability and enhance the permeability of the blood-brain barrier

Inactive Publication Date: 2015-05-27
HARBIN INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, blood-brain barrier permeability and biological stability are two major problems that must be overcome in the development of natural active peptides to become clinical drugs, and they are still a big bottleneck for the transportation of peptide drugs to the central system

Method used

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  • Coupling oligoarginine and 2 site substituted endomorphin-1 analogue as well as synthetic method and application thereof
  • Coupling oligoarginine and 2 site substituted endomorphin-1 analogue as well as synthetic method and application thereof
  • Coupling oligoarginine and 2 site substituted endomorphin-1 analogue as well as synthetic method and application thereof

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Experimental program
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specific Embodiment approach 1

[0034] Specific embodiment 1: The structure of the endomorphin-1 analogue coupled with oligoarginine and 2-position substitution in this embodiment is as follows:

[0035]

[0036] Wherein AA is β-Pro, D-Ala or Sar, n is 2 or 5.

[0037]While the endomorphin-1 analog of this embodiment retains opioid affinity and agonist activity, it has higher biological stability and analgesic activity of peripheral administration than the parent endomorphin-1, and reduces gastrointestinal Road side effects and other advantages. Experiments have confirmed the importance of oligoarginine and unnatural amino acid combination modification method for improving drug utilization and efficacy, which provides broad prospects for the development of new neuropeptide drugs with medical value.

specific Embodiment approach 2

[0038] Specific embodiment 2: The synthesis method of coupling oligoarginine and 2-substituted endomorphin-1 analog in this embodiment is carried out according to the following steps:

[0039] 1. Pretreatment of "Fmoc"-protected Wang resin: put 1.2g of Fmoc-Arg(pbf)-Wang resin with one amino acid residue into the solid-phase synthesizer, add 8-12mL of dichloromethane and stir for 30min, depressurize Suction filtration until the solvent is drained;

[0040] 2. Remove the "Fmoc" protecting group: wash the swelled resin with DMF for 3 minutes, filter it under reduced pressure until it is drained, repeat 3 times;

[0041] Add 8-12 mL of piperidine / DMF deprotection solution with a concentration of 20% by volume to the resin, stir for 5 minutes and drain, repeat twice;

[0042] Then add 10-14 mL of piperidine / DMF deprotection solution with a concentration of 20% by volume, stir for 15 minutes, then drain the solvent, and finally wash with 8-12 mL of DMF to obtain a resin from which...

specific Embodiment approach 3

[0049] Embodiment 3: This embodiment differs from Embodiment 2 in that the molar weight of the amino acid protected by the "Fmoc" group in step 3 is 2.5 to 3 times the molar weight of the Fmoc-Arg(pbf)-Wang resin. Others are the same as in the second embodiment.

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Abstract

The invention discloses a coupling oligoarginine and 2 site substituted endomorphin-1 analogue as well as a synthetic method and application thereof, and relates to an endomorphin-1 analogue as well as a synthetic method and application thereof. The coupling oligoarginine and 2 site substituted endomorphin-1 analogue aims at solving the problems that endomorphin-1 is relatively low in biological stability and peripheral administration analgesic activity and has relatively large side effects on the gastrointestinal tract. The synthetic method comprises the following steps: I, pre-treating Wang resin which is protected by 'Fmoc'; II, removing 'Fmoc' protection groups; III, performing amino acid condensation reaction; IV, extending a peptide chain; V, cutting the peptide chain from the resin; and VI, desalting and purifying crude peptides. According to the endomorphin-1 analogue disclosed by the invention, the opioid affinity and agonist activity can be maintained; and meanwhile, the endomorphin-1 analogue has higher biological stability and peripheral administration analgesic activity than that of maternal endomorphin-1, also has the advantages of reducing the side effects of the gastrointestinal tract, and can be used for preparing polypeptide analgesic medicines.

Description

technical field [0001] The present invention relates to an endomorphin-1 analogue and its synthesis method and application. Background technique [0002] The study of neuropeptides on pain perception and pain modulation has always been one of the hotspots in neuroscience research. It has been found that a variety of neuropeptides play an important role in the transmission and modulation of pain information, and the most familiar one is the opioid peptide. [0003] In 1997, Zadina et al. discovered two endogenous ligands with high affinity and high selectivity for μ-opioid receptors from bovine brain, namely endomorphin-1 (Tyr-Pro-Trp-Phe- NH2, EM-1) and endomorphin-1 (Tyr-Pro-Phe-Phe-NH2, EM-2), thus becoming a new breakthrough in opioid peptide research. Endomorphins (EMs) participate in the regulation of pain, cardiovascular, respiratory, gastrointestinal, movement, behavior, endocrine and immune functions by binding to G protein-coupled μ-opioid receptors, but their mai...

Claims

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Application Information

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IPC IPC(8): C07K7/02C07K1/06C07K1/04A61K38/08A61P29/00
CPCY02P20/55
Inventor 王长林刁玉祥邱停停
Owner HARBIN INST OF TECH
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