A class of analogs of opioid and neuropeptide ff receptor multi-target molecule bn-9 and its preparation method and application

A BN-9, neuropeptide technology, applied in the field of biochemistry, to achieve the effect of improving analgesic activity

Active Publication Date: 2020-05-08
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is still room for further improvement in the druggability of the reported BN-9 analogues, such as in terms of analgesic dose and analgesic time.

Method used

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  • A class of analogs of opioid and neuropeptide ff receptor multi-target molecule bn-9 and its preparation method and application
  • A class of analogs of opioid and neuropeptide ff receptor multi-target molecule bn-9 and its preparation method and application
  • A class of analogs of opioid and neuropeptide ff receptor multi-target molecule bn-9 and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] The synthetic method of embodiment 1 compound 1-4:

[0063] Experimental reagent: resin is Rink-Amide-MBHA-Resin (substitution value S is 0.43mmol / g; Tianjin Nankai Hecheng Company), O-benzotriazole-N,N,N',N'-tetramethyl Urea-hexafluorophosphate (HBTU) (Shanghai Jier Biochemical Co., Ltd.), N-hydroxybenzotriazole (HOBt) (Shanghai Jier Biochemical Co., Ltd.), N,N-diisopropylethylamine (DIEA) ( Beijing Bailingwei), 1,8-diazabicycloundec-7-ene (DBU) (Beijing Bailingwei), ninhydrin is the product of Shanghai Reagent No. 3 Factory, dichloromethane (DCM), N,N-dichloromethane Methylformamide (DMF), hexahydropyridine (piperidine), methanol (MeOH) and pyridine were purchased from Tianjin No. 2 Reagent Factory, and trifluoroacetic acid (TFA), phenol (PhOH) and pyridine were all from Tianjin No. 1 Reagent Factory Products, and the above organic reagents are all re-distilled before use.

[0064] Experimental equipment: solid-phase peptide synthesizer (designed by our laboratory...

Embodiment 2

[0106] Example 2 The in vitro functional activity assay of compounds 1-4 to opioid and NPFF receptors:

[0107] In stable expression of Mu-, Delta-, Kappa-opioid and NPFF 1 and NPFF 2 In HEK293 cells of the receptor, the agonism of these five receptors was detected by examining the regulation of the multi-target cyclic peptide of the opioid and NPFF receptors on Forskolin-induced intracellular cyclic adenosine monophosphate (cAMP) accumulation active. The specific method is: stably expressing Mu-, Delta-, Kappa-opioid and NPFF 1 and NPFF 2 Recipient HEK293 cells were seeded in 24-well plates at 120,000 cells per well, and cultured in an incubator for more than 20 hours. At the beginning of the experiment, the cell culture medium was replaced with preheated serum-free medium containing 1 mM IBMX, and incubated at 37°C for 10 min. Then, 10 μl of the drug to be tested and 10 μM Forskolin (final concentration) were added to each well, and incubated at 37° C. for 30 minutes....

Embodiment 3

[0115] The in vivo analgesic activity assay of embodiment 3 compound 1-4:

[0116] The analgesic activity of these BN-9 analogues in vivo was detected by the photothermal tail-flick experiment of acute pain model mice by adopting two different levels of administration, central (lateral ventricle administration) and peripheral (subcutaneous administration).

[0117] Administration of the lateral ventricle at the central level requires prior implantation of the lateral ventricle to ensure the accuracy of the administration site and minimize the damage to the mice. The lateral ventricle implantation was carried out using a mouse stereotaxic instrument. Kunming male mice weighed 21±2 g. First, the mice were anesthetized by intraperitoneal injection of pentobarbital sodium (80 mg / kg), and all surgical instruments were prepared and sterilized. Then the hair of the operation area on the top of the mouse's head was clipped clean. Fix the head of the mouse on the stereotaxic apparat...

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Abstract

The invention relates to analogs of an opium and neuropeptide FF receptor multi-target molecule BN-9, and a preparation method and an application thereof. Cysteine (Cys) or D-cysteine (D-Cys) containing a mercapto side chain is introduced to the amino acid sequence of BN-9, and in-vitro functional experiment results show that four brand-new BN-9 analogs have multi-target agonistic activity to opioid and neuropeptide FF receptors, the central and peripheral analgesic effects and the action time of parts of the analogs are improved, and all the analogs can be used to mediate the non-tolerant analgesic effect. The brand-new BN-9 analogs can be used to prepare analgesic drugs.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, and relates to a class of opioid / neuropeptide FF receptor multi-target peptide molecule BN-9 analogs and a preparation method and application thereof. Background technique [0002] Pain treatment is a major challenge facing the world. For the needs of clinical research, the International Association for the Study of Pain defines pain as "the uncomfortable perception and psychological sensation caused by actual or potential damage to body tissues". Pain under physiological conditions is used as a protective mechanism to prevent the body from being harmed, but pain under pathological conditions not only brings pain to the patient, but also causes damage to the central nervous system, circulatory, respiratory, endocrine, digestive and autonomic nervous systems of the human body. Adverse effects, and even some severe pain, can threaten the patient's life. In particular, chronic pain is a clinic...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C07K1/06C07K1/04A61K38/33A61K38/07A61K38/08A61P25/04
CPCA61K38/00A61P25/04C07K5/1016C07K7/06C07K14/70C07K2319/00
Inventor 方泉张梦娜王锐许彪石学睿
Owner LANZHOU UNIVERSITY
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