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Synthesis and application of multi-site modified endomorphin-1 analogue

An endomorphin, multi-site technology, applied in the field of biomedicine, can solve the problems of short action time and poor enzymatic stability.

Active Publication Date: 2013-07-24
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] While exerting its analgesic effect, endomorphin-1 also has shortcomings such as short action time and poor enzymatic stability, which limit its clinical application

Method used

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  • Synthesis and application of multi-site modified endomorphin-1 analogue
  • Synthesis and application of multi-site modified endomorphin-1 analogue
  • Synthesis and application of multi-site modified endomorphin-1 analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Embodiment one, the synthesis of [DPPM]-EM-1

[0107] (1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropionic acid amide

[0108] Dissolve 1 mole of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropionic acid in anhydrous dichloromethane, and add 4 moles of N,N-diisopropylethyl Baseamine, 1.45 moles of 1-hydroxybenzotriazole, 1.6 moles of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stirred and dissolved fully, added 1.2 moles of ammonia water, and reacted at room temperature for 12 hours Add dichloromethane to dilute after the reaction is finished, wash three times with 5% citric acid solution, wash three times with saturated sodium bicarbonate, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain a white solid product——N- tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropanoic acid; 90% yield.

[0109] (2) Synthesis of 3-amino-2-methenyl-3-phenylpropionic acid amide

[...

Embodiment 2

[0124] Embodiment two, the preparation of [DPFM]-EM-1

[0125] (1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(2-furan)propionic acid amide

[0126] Dissolve 1 mole of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(2-furan)propionic acid in anhydrous dichloromethane, and add 4 moles of N,N-dichloromethane successively under stirring at 0°C Isopropylethylamine, 1.45 moles of 1-hydroxybenzotriazole, 1.6 moles of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, stirred and fully dissolved, then added 1.2 moles of ammonia water, React at room temperature for 12 hours; add dichloromethane to dilute after the reaction, wash three times with 5% citric acid solution, wash three times with saturated sodium bicarbonate, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain a white solid product - N-tert-butoxycarbonyl-3-amino-2-methenyl-3-(2-furan)propionic acid, yield 88%.

[0127] (2) Synthesis of 3-amino-2...

Embodiment 3

[0142] Embodiment three, the synthesis of [DSPM]-EM-1

[0143] (1) Synthesis of N-tert-butoxycarbonyl-3-amino-2-methenyl-3-phenylpropionic acid amide: same as Example 1.

[0144] (2) Synthesis of 3-amino-2-methenyl-3-phenylpropionic acid amide: same as Example 1.

[0145] (3) Synthesis of N-tert-butoxycarbonyl-tryptophan-3-amino-2-methenyl-3-phenylpropionic acid amide: same as Example 1.

[0146] (4) Synthesis of N-tert-butoxycarbonyl-2,6-dimethyltyrosine-(S)β-proline

[0147] Dissolve 1 mole of N-tert-butoxycarbonyl-2,6-dimethyltyrosine in anhydrous dichloromethane, add 4 moles of N,N-diisopropylethylamine successively under stirring at 0°C, 1.45 moles 1-Hydroxybenzotriazole, 1.6 moles of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, after fully dissolved by stirring, add 1.2 moles of (S) β-proline saturated carbonic acid Sodium hydrogen solution, react at room temperature for 12 hours, add dichloromethane to dilute after the reaction, wash three times with 5% citric aci...

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Abstract

The invention provides synthesis and application of multi-site modified endomorphin-1 analogues, belonging to a biological medicine field. The endomorphin-1 analogues are prepared by substituting a first amino acid of endomorphin-1 through tyrosine or 2,6-dimethyl tyrosine, substituting a second amino acid through proline or (S / R) beta-proline, and substituting a forth amino acid through phenyl, and 2-furyl substituted alpha-alkenyl-beta-amino acid respectively. By a radioligand receptor binding experiment, in vitro organ biological detection, a cAMP accumulation experiment, and an in vitro enzymolysis stability and warm water bath tail flick analgesic experiments, the multi-site modified endomorphin-1 analogues in the invention are performed pharmacological activity identification. A result shows that: compared with endomorphin-1, the novel multi-site modified endomorphin-1 analogues has advantages of high affinity, high enzymolysis stability and high analgesic activity, and has a high application value for designing and synthesizing polypeptide analgesic drugs.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a class of endomorphin-1 (Endomorphin-1, EM-1) analogs and a synthesis method thereof, in particular to a multi-site modified endomorphin-1 analog and its synthesis Method; the present invention also relates to the application of the endomorphin-1 analog in the preparation of analgesic drugs. Background technique [0002] "Pain" refers to the nociceptive sensation inside the patient's body, which includes the pain sensation caused by noxious stimuli acting on the body and the body's pain response to noxious stimuli. Long-term pain brings pain and anxiety to patients, and severe pain can also cause insomnia or other biological dysfunction, affecting the quality of life of patients. Therefore, the research and development of pain drugs has always been a global hotspot and difficulty. The analgesic drugs currently used clinically mainly include non-steroidal anti-inflammatory drugs (antipy...

Claims

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Application Information

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IPC IPC(8): C07K5/023A61K38/07A61P29/00
Inventor 王锐刘鑫王媛邢燕红赵德鹏
Owner LANZHOU UNIVERSITY
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