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C-end phenylalanine p-amino modified endomorphine-1 analog and preparation and application thereof

A technology of amination modification and terminal phenylalanine, applied in the field of biochemistry, can solve the problems of poor enzymatic stability and short analgesic time of endomorphin

Inactive Publication Date: 2012-09-12
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these opioids cannot be used clinically because opioids can cause many side effects in pain patients, including the following: constipation, addiction, tolerance, vomiting, and breathing Inhibition, etc.
There are several reasons why endomorphins cannot become clinical drugs because endomorphins have a relatively short analgesic time, relatively poor enzymatic stability, weak ability to pass through the BBB, and no drug effect when taken orally.

Method used

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  • C-end phenylalanine p-amino modified endomorphine-1 analog and preparation and application thereof
  • C-end phenylalanine p-amino modified endomorphine-1 analog and preparation and application thereof
  • C-end phenylalanine p-amino modified endomorphine-1 analog and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] (1) Boc-Phe (4-NO 2 )-NH 2 Synthesis

[0099] 10mmol tert-butoxycarbonyl protected p-nitrophenylalanine (Boc-Phe(4-NO 2 )-OH) in 100mL THF, add 10mmol of HOBT, stir to dissolve completely, after the color of the solution turns reddish brown, add 10mmol of DIEA, stir for 12 hours, remove THF by rotary evaporation, dissolve in water , extracted with ethyl acetate, the organic phase was successively washed with citric acid solution with a mass concentration of 5%, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid, namely Boc-Phe ( 4-NO 2 )-NH 2 ; Yield 90%.

[0100] (2) Synthesis of monobenzyloxycarbonylated amidinopyrazole hydrochloride

[0101] Completely dissolve 10mmol of amidinopyrazole hydrochloride in dichloromethane, add 20mmol of Cbz-CI, stir and react for 10 minutes, then add triethylamine with a molar weight of 20mmol of amidinopyrazole hydrochloride, at 0°C ...

Embodiment 2

[0130] (1) Boc-Phe (4-NO 2 )-NH 2 Synthesis

[0131] 10mmol Boc-Phe (4-NO 2 )-OH ) was dissolved in 100mL tetrahydrofuran, and 11mmol of HOBT was added, and stirred to dissolve completely. After the color of the solution turned reddish brown, 12mmol of DIEA (N,N-diisopropylethylamine) was added, and the reaction was stirred for 14 hours , dissolved in water after removal of tetrahydrofuran by rotary evaporation, extracted with ethyl acetate, the organic phase was successively washed with 5% citric acid solution, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain white solid, namely Boc-Phe (4-NO 2 )-NH 2 ; Yield 95%.

[0132] (2) Synthesis of monobenzyloxycarbonylated amidinopyrazole hydrochloride

[0133] Completely dissolve 10mmol of amidinopyrazole hydrochloride in dichloromethane, add 40mmol of Cbz-CI, stir and react for 20 minutes, then add triethylamine with a molar mass of...

Embodiment 3

[0160] (1) Boc-Phe (4-NO 2 )-NH 2 Synthesis

[0161] 10mmol tert-butoxycarbonyl protected p-nitrophenylalanine (Boc-Phe(4-NO 2 )-OH) was dissolved in 100mL THF, added 13mmol of HOBT, stirred to dissolve completely, after the color of the solution turned reddish brown, then added 20mmol of DIEA, stirred for 20 hours, rotary evaporated to remove THF and dissolved in water , extracted with ethyl acetate, the organic phase was successively washed with citric acid solution with a mass concentration of 5%, saturated sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a white solid, namely Boc-Phe ( 4-NO 2 )-NH 2 ; Yield 94%.

[0162] (2) Synthesis of monobenzyloxycarbonylated amidinopyrazole hydrochloride

[0163] Dissolve 10mmol of amidinylpyrazole hydrochloride completely in dichloromethane, add 45mmol of Cbz-CI (benzyloxycarbonyl chloride), stir for 25 minutes, and then add 54mmol of amidinylpyrazole hy...

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Abstract

The invention provides a C-end phenylalanine p-amino modified endomorphine-1 analog. The N end of endomorphine-1 is modified by using guanidyl, Pro-Typ at the 2nd and 3rd positions of the endomorphine-1 is substituted by D-Ala-Gly, the benzene ring para-position at the 4th position is modified by using amino, and the novel analog [GAGPNH2]-EM-1 of the endomorphine-1 is synthesized by a liquid phase synthesis method. A series of physiological and pharmacological activity identification is performed on the analog through radioligand receptor binding experiment, in vitro enzymolysis stability experiment and warm bath drift analgesia experiment, and the results show that the analog has high affinity, high enzymolysis stability, high blood-brain barrier permeating capability and low side effect compared with parents of the analog. Therefore, the analog which is used as an active substance and used for preparing clinical analgesia medicaments has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, and relates to a novel endomorphin-1 analogue modified by para-amination of C-terminal phenylalanine; the invention also relates to a preparation method of the endomorphin-1 analogue and its application in the preparation of analgesic drugs. Background technique [0002] In 1997, Zadina, a neurobiologist at Durham University in the United States, and his colleagues isolated and purified from bovine brains by immunohistochemical screening of peptide libraries. Hackler, L.; Ge, L.J.; Kastin, A.J. A potent and selective endogenous agonist for the μ-opiate receptor. Nature .1997, 386: 499-502). The ligand is called an endogenous opioid peptide, and its structure has been found in two types: endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ). However, studies have shown that endomorphin-2 has naturally weak therapeutic properties, its analgesic efficacy is lower...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/107A61K38/07A61P29/00
Inventor 王锐梁媛王一青
Owner LANZHOU UNIVERSITY
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