Use of 7-alkoxy fangchinoline base compounds in the preparation of medicines for treating and improving depressive symptoms

A technology of fangchinoline base and compound, applied in the field of medicine, can solve the problems of complex pathogenesis of depression, single effect of western medicine, delayed onset of effect, etc.

Active Publication Date: 2021-02-05
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The pathogenesis of depression is complex, the clinical symptoms are diverse, and the existing western medicine has a single effect, and there are insufficient treatments for depression, a complex disease caused by multiple factors.
Antidepressants currently used clinically have "bottleneck" problems that need to be solved urgently, such as "delayed onset of action", "low effective rate", and "adverse reactions".

Method used

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  • Use of 7-alkoxy fangchinoline base compounds in the preparation of medicines for treating and improving depressive symptoms
  • Use of 7-alkoxy fangchinoline base compounds in the preparation of medicines for treating and improving depressive symptoms
  • Use of 7-alkoxy fangchinoline base compounds in the preparation of medicines for treating and improving depressive symptoms

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1G

[0053] Example 1 Determination of GSK-3β activity

[0054] The phosphorylation level of GSK-3β was determined by Z’-LYTE assay from Life Technologies. The method belongs to fluorescence analysis and is based on fluorescence resonance energy transfer (FRET). The system uses human recombinant GSK-3 (N-terminal 6 histidine tagged and H350L mutant recombinase, purchased from Millipore, (Billerica, MA, USA) as a polypeptide substrate with fluorophores at both ends. If the polypeptide If the substrate remains intact, FRET can occur. If the kinase phosphorylates the polypeptide substrate, adding a protease to the system cannot cleave the polypeptide, and the system still undergoes FRET. But if the substrate is not phosphorylated, the polypeptide will be Protease cleavage, so that the FRET signal is eliminated. The detection is carried out in a 384-well plate. The final volume of the reaction is 10 μl containing 2nM enzyme, 50mM Hepes pH7.5, 50mM MgCl2, 1mM EGTA and 0.05% Brij-35, ...

Embodiment 2

[0061] Improvement / therapeutic effect of compounds 1-8 on depressive behavior in rats with chronic unpredictable stress (CUS) , Comparison of efficacy of 12-acetoxy berbamine and 12-(4-oxyethyl)-butoxy berbamine.

[0062] The chronic unpredictable stress model is often used as a model of depression. Experimental method: Stimulation content includes: forced swimming (10°C, 6min), tail clamping (1cm from the base of the tail, 1min), water deprivation (24h), fasting (24h), solitary raising (24h), tail suspension (1h) , braking (2h), high-speed horizontal shock (120 times / min, 1h), plantar electric shock for 45min (average 1mA, duration 1s, 1 time / 1min). The chronic stress course was 22 days in total, once a day, and a stimulation method was randomly selected for stimulation. Time: between 9:00 am and 2:00 pm. From the 15th day of stress, 60 minutes before the stress every day, the animals in each group were given the test drug and double distilled water (blank group and CUS mo...

Embodiment 3

[0079] Embodiment 3, the effect of bisbenzylisoquinoline derivative YH-200 (compound 3) shown in formula (I) on the phosphorylation level of GSK-3β in the mouse prefrontal cortex, hippocampus, striatum and hypothalamus (Mean±SE, n=4); *P<0.05, **P<0.01 compared with the control group (Student's t-test).

[0080] The ICR mice were taken and given the test drug and solvent by intragastric administration for 1 hour, then the brain was decapitated, and the prefrontal cortex, hippocampus, striatum and hypothalamus were separated and collected for protein electrophoresis (western blot). The result is as figure 1 As shown, compared with the blank control group, intragastric administration of 30mg / kg YH-200 had no significant effect on the p-GSK-3β and total-GSK-3β in the prefrontal cortex, hippocampus and striatum of the mice, However, the level of p-GSK-3β in the hypothalamus was significantly increased. The 60mg / kg dose of YH-200 significantly increased the p-GSK-3β level in the...

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Abstract

The invention provides a new application of 7-alkoxy fangchinoline derivatives or pharmaceutically acceptable salts thereof in the preparation of GSK-3β inhibitors and in the treatment and improvement of depressive symptoms. The compound 1‑8 with the structure of formula (I) has shown the effect of promoting the phosphorylation of glycogen synthesis kinase ‑3β (GSK‑3β) at the level of cells and whole animals, and then inhibiting its activity; the results of animal experiments found that compound 1‑8 May be enhanced by 5‑HT 1A Receptor and melatonin receptor function, inhibits 5‑HT 2A Receptor function, inhibit GSK‑3β activity, improve depressive symptoms such as hopelessness, loss of pleasure, anxiety and sleep disorders.

Description

technical field [0001] The invention relates to a new application of 7-alkoxy fangchinoline compound, especially its application in the preparation of medicines for treating and improving depression, and belongs to the field of medicine. Background technique [0002] In the 7-alkoxy tetrandrine compound (described in the formula (I) structure), tetrandrine (also known as tetrandrine, tetrandrine), tetrandrine (7-demethyl tetrandrine, Also known as Chinese tetrandrine, fangchinoline), berbamine (12-desmethyl tetrandrine, trade name: white amine, berbamine) and 5-bromo tetradrine (trade name: Bromotetrandrine, 5-bromotetrandrine ) have been studied more; among them, tetrandrine, tetrandrine and berbamine are natural products, while 5-bromotetrandrine is a semi-synthetic product. [0003] It is known in the prior art that the uses of berbamine include: antipruritic (KR2006000127-A, KR1126592-B1); anti-osteoporosis (CN1357346-A); anti-chloroquine-resistant Plasmodium (JP2000143...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4748A61P25/24A61P25/20
Inventor 张永鹤张雪琼盛兆福
Owner PEKING UNIV
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