Cyclic endomorphin-1 analog with high enzymolysis stability and analgesic activity and application thereof

An endomorphin and analog technology, which can be applied to medical preparations containing active ingredients, cyclic peptide components, peptides, etc., can solve the problems of short analgesic effect time and poor enzymatic stability.

Active Publication Date: 2020-07-03
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the shortcomings of endomorphin-1, such as short analgesic action time and poor enzymatic stability, limit its clinical application.

Method used

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  • Cyclic endomorphin-1 analog with high enzymolysis stability and analgesic activity and application thereof
  • Cyclic endomorphin-1 analog with high enzymolysis stability and analgesic activity and application thereof
  • Cyclic endomorphin-1 analog with high enzymolysis stability and analgesic activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Embodiment 1: the synthesis of Analog3

[0075] (1) Solid-phase synthesis of linear peptides: put 0.3 mmol of Rink amide MBHA resin in a solid-phase synthesizer, add 10 mL of redistilled DCM to swell and activate, and use DMF to elute the DCM, and use it when the resin is in good condition. DMF eluting indene detection reagent; sequentially add 0.9 mmol of Fmoc-protected cyclic endomorphin-1 analog 1-position amino acid, HOBt, HBTU, and 0.3 mL of DIEA in DMF solution, and react for 40 min under the protection of inert gas; After elution of unreacted drugs and reagents in the DMF reaction system, check whether the amino acid is connected to the resin; after that, the connection of the 2-6 amino acid is the same as the above process, and the linear peptide is obtained;

[0076] (2) Cyclization of linear peptides: transfer the resin connected with linear peptides in step (1) to a round bottom flask, add CCl with a volume ratio of 37:2:1 to 1g of resin corresponding to 15mL...

Embodiment 2

[0080] Embodiment 2: the synthesis of Analog4

[0081] (1) Solid-phase synthesis of linear peptides: put 0.3mmol Rink amide MBHA resin in a solid-phase synthesizer, add 12mL redistilled DCM to swell and activate, after DMF elutes DCM, if the resin is in good condition, wash it with DMF. Indene detection reagent; sequentially add 0.6mmol of Fmoc-protected 1-position amino acid of Analog4, HOBt, HBTU, and 0.2mL of DIEA in DMF solution, and react for 50min under the protection of inert gas; DMF elutes unreacted drugs in the reaction system Check whether the amino acid is connected to the resin after indene with the reagent; after that, the insertion of the 2-6 amino acid is the same as the above process to obtain a linear peptide;

[0082] (2) Cyclization of linear peptides: transfer the resin connected with linear peptides in step (1) to a round bottom flask, add CCl with a volume ratio of 37:2:1 to 1g of resin corresponding to 15mL of solvent under magnetic stirring 3 , HAC an...

Embodiment 3

[0086] Embodiment 3: the synthesis of Analog5

[0087](1) Solid-phase synthesis of linear peptides: put 0.3mmol of Rink amide MBHA resin in a solid-phase synthesizer, add 15mL of redistilled DCM for swelling and activation, and use DMF to elute DCM. If the resin is in good condition, use DMF elutes the indene detection reagent; sequentially add 0.45mmol of Fmoc-protected 1-position amino acid of cyclic Analog5, HOBt, HBTU, and 0.1mL of DIEA in DMF, react for 60min under the protection of inert gas; DMF elution reaction system After the unreacted drugs and reagents, check whether the amino acid is connected to the resin; after that, the connection of the 2-6 amino acid is the same as the above process, and the linear peptide is obtained;

[0088] (2) Cyclization of linear peptides: transfer the resin connected with linear peptides in step (1) to a round bottom flask, add CCl with a volume ratio of 37:2:1 to 1g of resin corresponding to 15mL of solvent under magnetic stirring 3...

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Abstract

The invention discloses a cyclic endomorphin-1 analog with high enzymolysis stability and analgesic activity, and belongs to the field of biological medicines. The cyclic endomorphin-1 analog is obtained by taking ZH853 as a template and carrying out D-Dap substitution on the 2nd-position D-Lys and / or carrying out terminal carboxylation modification on the 6th-position Gly of the cyclic endomorphin-1 analog respectively; and an analgesic activity research experiment and an enzymolysis stability experiment show that the cyclic endomorphin-1 analog has high enzymolysis stability and analgesic activity, and the analgesic effect is faster. D-Dap with three methylene groups less than D-Lys is introduced to the 2nd position of Analog4 and Analog5, so that the formed ring is small, the rigidity is stronger than that the rigidity of ZH853, and thus the enzymatic hydrolysis stability is stronger. The analgesic effect is faster because the rigidity enhancement can further enhance the ability topenetrate a blood-brain barrier. Therefore, the cyclic endomorphin-1 analog has a good application prospect in preparation of clinical analgesic drugs.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a class of cyclic endomorphin-1 analogs, in particular to a class of cyclic endomorphin-1 analogs with strong enzymatic stability and analgesic activity. The invention relates to the application of the cyclic endomorphin-1 analog in the preparation of clinical analgesic drugs. Background technique [0002] Opioid analgesics mainly exert their analgesic effect by binding to μ opioid receptors (MOR). Endomorphins have been extensively studied as endogenous ligands of MOR. Studies have shown that endomorphin participates in the regulation of many functions including pain perception, breathing, cardiovascular, gastrointestinal, endocrine, etc. by combining with G protein-coupled MOR, but its main role is reflected in the analgesic function. Endomorphins include endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 , EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 , EM-2), due to the therapeutic properties of...

Claims

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Application Information

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IPC IPC(8): C07K7/56C07K1/08C07K1/06C07K1/04C07K1/14C07K1/20A61K38/12A61P25/04
CPCC07K7/56A61P25/04A61K38/00Y02P20/55
Inventor 王锐刘鑫王媛罗克耀
Owner LANZHOU UNIVERSITY
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