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Combined chemical modified endomorphin-1 and method for preparing same

An endomorphin and compound technology, which is applied in the field of combinatorial chemically modified endomorphin-1 and its preparation, can solve the problems of rare analgesic analogs, short duration of analgesia, lack of oral activity and the like, Achieve the effects of improving bioavailability, prolonging analgesic action time, and simplifying synthetic routes

Active Publication Date: 2008-03-05
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, EM-1 also has disadvantages similar to other endogenous opioid peptides, such as short duration of analgesia, lack of oral activity, poor enzymatic stability, rapid degradation in blood and brain, and short half-life. The presence of the BBB also hinders their access to the CNS to exert their effects, thus limiting the use of endomorphins as therapeutic drugs
Although many endomorphin analogues have been synthesized so far, there are few analogues that can be injected into the CNS to produce analgesia

Method used

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  • Combined chemical modified endomorphin-1 and method for preparing same
  • Combined chemical modified endomorphin-1 and method for preparing same
  • Combined chemical modified endomorphin-1 and method for preparing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Synthesis of Analogue [GMLPC]-EM-1

[0037] Reaction I: Synthesis of Boc-Tyr(Me)-OH(b)

[0038] Compound a (Boc-Tyr-OH) and 4 times the amount of NaH were respectively dissolved in anhydrous THF, protected by Ar, and the solution of compound a was slowly added dropwise to NaH / THF under stirring in an ice-salt bath. After reacting at -15°C for 30 min, excess CH3I was slowly added dropwise to the reaction system, and stirred overnight at room temperature. After the reaction is complete, extract the reaction with ice water at 0°C, concentrate THF under reduced pressure, leave the aqueous phase at the bottom of the bottle, add a mixture of ether / water (1:3), the product remains in the aqueous phase, and saturate with NaHCO 3 Wash the ether layer twice, combine with the previous aqueous phase, adjust the pH value of the aqueous phase to 3-4 with 20% citric acid, extract the aqueous phase with ethyl acetate three times, combine the ethyl acetate layers, and wash w...

Embodiment 2

[0059] Example 2: Synthesis of Analogue [GMDPC]-EM-1

[0060] Reaction I: See Example 1.

[0061] Reaction II: Synthesis of Boc-Tyr(Me)-D-Pro-OH(d)

[0062] Compound b and a 1.1-fold excess of HOSu were dissolved in anhydrous THF, and after stirring in an ice bath for 10 min, a pre-cooled 1.1-fold excess of DCC / THF solution was slowly added dropwise, reacted in an ice bath for 30 min, then removed the ice bath, and reacted at room temperature for 6 h. The DCU precipitate was removed by vacuum filtration to obtain the activated ester [Boc-Tyr(Me)-OSu] solution of compound b. Under ice-bath stirring, dropwise add the NaHCO of the compound c (D-Pro) of equimolar amount to the filtrate 3 solution (pH=8-9), reacted overnight. After the reaction was complete, concentrate under reduced pressure to remove THF, add a large amount of ethyl acetate to dissolve the residue, wash with 5% citric acid and saturated NaCl three times, dry over anhydrous sodium sulfate, and concentrate. Pur...

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Abstract

The present invention is four analogs of endomorphin-1, [GMLPC]-FM-1, [GMLDC]-EM-1, [GMDPC]-EM-1 and [GMDDC]-EM-1, prepared through liquid phase synthesis and their preparation process. Serial pharmacological activity identifying measurements shows that these four analogs have enzymolysis stability in brain plasmalemma and blood serum of mouse obviously higher than their precursor, longer pain relieving time, and higher integral liposolubility. The present invention is significant for developing endomorphin-1 into clinical polypeptide analgesic.

Description

technical field [0001] The present invention relates to a class of novel analogs [GMLPC]-EM-1, [GMLDC]-EM-1, [GMDPC]-EM-1 and [GMDDC] of endomorphin-1 (Endomorphin-1, EM-1) ]-EM-1 and its preparation method. Background technique [0002] Endomorphin 1 (Tyr-Pro-Trp-Phe-NH 2 , EM-1) and endomorphin 2 (Tyr-Pro-Phe-Phe-NH 2 , EM-2) are two endogenous opioid peptides that selectively agonize mu opioid receptors with high efficiency. Studies have found that endomorphins can participate in the regulation of many functions such as pain perception, cardiovascular, respiratory, gastrointestinal, exercise, behavior, endocrine and immunity through binding to G protein-coupled μ opioid receptors, but its main role is Potent analgesic activity, can produce analgesic effect comparable to that of morphine with less side effects, especially they also show obvious analgesic activity in animal models of neuralgia. Because EM-1 has better therapeutic properties than EM-2, such as the separa...

Claims

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Application Information

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IPC IPC(8): C07K5/107C07K7/06A61K31/07A61K38/08A61P25/04
CPCY02P20/55
Inventor 王锐刘红美刘雪锋
Owner LANZHOU UNIVERSITY
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