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Split type hybrid peptides based on endomorphin 2 and NPFF (Neuropeptide FF) receptor antagonist RF9, as well as synthetic method and application thereof

A receptor antagonist, endomorphin technology, applied in the field of biochemistry, can solve the problems of limited clinical application, constipation, analgesic tolerance, etc.

Active Publication Date: 2015-06-17
SHANGHAI TIANCI LIFE SCI DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the most widely used opioid analgesic drugs are often accompanied by some side effects, such as analgesic tolerance, constipation and addiction, which greatly limit their clinical application

Method used

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  • Split type hybrid peptides based on endomorphin 2 and NPFF (Neuropeptide FF) receptor antagonist RF9, as well as synthetic method and application thereof
  • Split type hybrid peptides based on endomorphin 2 and NPFF (Neuropeptide FF) receptor antagonist RF9, as well as synthetic method and application thereof
  • Split type hybrid peptides based on endomorphin 2 and NPFF (Neuropeptide FF) receptor antagonist RF9, as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] The synthesis of embodiment 1, EKR

[0092] (1) Resin pretreatment: Weigh 800 mg of Rink-Amide-MBHA resin with a substitution value of 0.43 mmol / g and add it to the synthesizer, then add DCM and stir for 30 min to fully swell the resin and dry the solvent under reduced pressure.

[0093](2) Removal of Fmoc group protection: Add a mixed solution of hexahydropyridine, DBU, and DMF (the volume ratio of the three is 1:1:98) to the resin that has been swollen and drained of solvent, stir for 5 minutes and then pump Dry, repeat 3 times and then drain. The DMF that was added at the end was stirred for 3 min and then sucked dry. This was repeated 4 times to obtain a resin sample from which the protection of the Fmoc group was removed.

[0094] (3) Indene detection: add to the test tube in the following order: resin sample, 0.1 ml reagent , 0.2ml reagent , 0.1 ml reagent , observe after boiling water bath for 3-10 min. Both the solution and the resin are blue, indicating...

Embodiment 2

[0103] Embodiment two, the synthesis of RKE

[0104] (1) Resin pretreatment: Add 500 mg of Rink-Amide-MBHA resin with a substitution value of 0.4 mmol / g into the synthesizer, and the treatment process is the same as in Example 1.

[0105] (2) Removal of Fmoc group protection: Same as Example 1.

[0106] (3) Indene detection: same as Example 1.

[0107] (4) Condensation of linker Lys: Same as Example 1.

[0108] (5) Main chain condensation: The peptide resin obtained in step (4) from which the Fmoc protective group has been removed is sequentially completed in steps (2) and (3) to complete Fmoc-Phe-OH, Fmoc-Arg(Pbf)-OH , Condensation of 1-adamantanic acid and deprotection of Fmoc group to obtain peptide resin sample 1-adamantanylation-Phe-Arg(Pbf)-Lys(Mtt)-Resin.

[0109] (6) Removal of the Lys side chain amino Mtt protecting group: After the resin obtained in step (5) is drained of solvent, add 1%-1.5% TFA / DCM solution, stir for 2 min and then drain, repeat 50 times Drain....

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Abstract

The invention provides split type hybrid peptides EKR and RKE based on an endogenous opioid peptide endomorphin 2 and a NPFF (Neuropeptide FF) receptor antagonist RF9 constructed by chemical attachment through Lys. In-vitro functional detection shows that both the EKR and the RKE can be used for activating a Mu opioid receptor; both the EKR and the RKE are opioid agonists; in-vivo activity detection shows that obvious central analgesia activity can be caused by lateral cerebral ventricle injection of both the EKR and the RKE; the analgesia EC50 values of the EKR and the RKE are 6.127 (5.372, 6.989) n mol and 4.523 (4.043, 5.058) n mol respectively; furthermore, a common side effect, namely constipation, of opioid analgesic drugs cannot be caused by lateral cerebral ventricle injection of the EKR and the RKE in the effective analgesic dosage range (5, 10, 20 n mol); therefore, the EKR and the RKE can mediate low-side effect analgesic activity; and thus, the EKR and the RKE have potential application value for clinical pain treatment.

Description

technical field [0001] The invention belongs to the field of biochemical technology, and relates to a class of bifurcated hybrid peptides based on endogenous opioid peptide-endomorphin 2 and NPFF receptor antagonist RF9 and a synthesis method thereof. The present invention also relates to the pharmacological activities of the above-mentioned forked hybrid peptides EKR and RKE in receptor stimulation, pain regulation, tolerance and addiction, constipation and the like. Background technique [0002] Pain plays an important role in clinical medical treatment and improving the quality of life of patients. At present, the most widely used opioid analgesic drugs are often accompanied by some side effects, such as analgesic tolerance, constipation and addiction, which greatly limit their clinical application. Therefore, research and development of highly effective analgesic new drugs with low side effects have broad application prospects. [0003] Studies have shown that th...

Claims

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Application Information

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IPC IPC(8): C07K7/02C07K1/06C07K1/04A61K38/08A61P25/04
CPCY02P20/55
Inventor 王锐方泉李宁韩政岚王子龙
Owner SHANGHAI TIANCI LIFE SCI DEV CO LTD
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