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Use of genistein derivative in improvement of dysfunction of learning and memory at multiple targets

A drug and pharmacy technology, applied in the field of genistein derivatives, can solve problems such as difficulty in achieving therapeutic effects with single-target drugs and complex pathogenesis of AD

Inactive Publication Date: 2018-07-03
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Due to the complex pathogenesis of AD, it is difficult for single-target drugs to achieve ideal therapeutic effects

Method used

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  • Use of genistein derivative in improvement of dysfunction of learning and memory at multiple targets
  • Use of genistein derivative in improvement of dysfunction of learning and memory at multiple targets
  • Use of genistein derivative in improvement of dysfunction of learning and memory at multiple targets

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1. Research on the inhibitory effect of DL0410-3 on ACHE and BuCHE activities in vitro

[0050] DL0410-3 is the mesylate salt of WS1102001.

[0051] Methods: The AChE inhibitor screening model and the BuChE inhibitor screening model were established by DTNB method, and the inhibitory activity of DL0410-3 on AChE and BuChE was evaluated at 0.08-50 μmol / L, and the IC was calculated 50 . Repeat three times, calculate the mean and SD value.

[0052] Results: DL0410-3 has inhibitory effect on both AChE and BuChE, the IC of AChE and BuChE 50 See Table 1, figure 1 and figure 2 , wherein AChE inhibition means acetylcholinesterase inhibition, and BuChE inhibition means butyrylcholinesterase inhibition.

[0053] Table 1. IC of DL0410-3 inhibiting ACHE and BuCHE activities 50

[0054]

Embodiment 2

[0055] Example 2 Study on the Effect of DL0410-3 on Neuroinflammation

[0056] Method: DL0410-3 with a final concentration of 10 and 2 μmol / L, Exelon and nicotine with a final concentration of 10 μmol / L were co-incubated with rat cerebral cortical microglial cells for 2 hours, except for the blank control group, the model group Added LPS at a final concentration of 1 μg / ml to the treatment group and the treatment group, and continued to incubate for 24 hours, then collected the cell supernatant, and determined the contents of IL-1β and IL-6 in the cell supernatant by Elisa method.

[0057] Results: Compared with the normal group, after 24 hours of LPS stimulation, the contents of IL-1β and IL-6 in the supernatant of the cells in the model group were significantly increased (p image 3 and Figure 4 .

[0058] Table 2. The effect of DL0410-3 on the secretion of IL-1β and IL-6 from activated microglial cells

[0059]

[0060] ## Compared with the normal group, P* Compared w...

Embodiment 3

[0061] Example 3. Based on the established compound anti-Alzheimer's disease (AD) drug target prediction system, it was predicted that DL0410-3 can regulate AChE, BuChE, 5-HT4, GABA A, MAO B, α7nAChR and other AD-related polymorphisms. target drug effect.

[0062] The established prediction system has 51 anti-AD drug targets, and its website is: http: / / rcidm.org / AlzhCPI / index.html. The system was used to predict and verify the targets of DL0410-3. It was found that DL0410-3 has multi-target pharmacodynamic characteristics. In addition to AChE and BuChE, the targets also include 5-HT4, GABA A, MAO B, α7nAChR. For experimental verification results, see figure 1 and figure 2 . Published related research papers as follows:

[0063] [1]Discovery of multitarget-directed ligands against Alzheimer's disease through systematic prediction of chemical-protein interactions.J ChemInf Model.2015Jan 26;55(1):149-64.

[0064] [2] Inhibition of acetylcholinesterase by two genistein der...

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Abstract

The invention discloses a genistein derivative (5-hydroxy-7-O-ethylpiperidine isoflavone, DL0410-3, WS1102001). The genistein derivative has relatively strong inhibiting effects to the activities of acetylcholin esterase and butyrylcholine esterase and further has the efficacies of protecting nerves, improving oxidative stress and adjusting neuroinflammation. A prediction result of a compound anti-Alzheimer disease target prediction system shows that DL0410-3 is further capable of inhibiting the expression of APP and the activities of 5-HT4, GABA A and MAO B and activating alpha7nAChR. An animal experiment result shows that DL0410-3 is relatively low in toxicity and capable of penetrating through blood brain barriers; DL0410-3 is capable of obviously improving the dementia of mice caused due to scopolamine and enhancing the learning and memory functions under a safe dose; DL0410-3 is capable of obviously improving the dysfunction of learning and memory of mice caused due to galactose,adjusting neuroinflammation and alleviating oxidative stress injury; and DL0410-3 is capable of obviously improving dysfunction of learning and memory of APP / PS1 transgenic mice and obviously enhancing LTP of a Schaffer-CA1 region of extracorporeal hippocampal slices of the APP / PS1 transgenic mice.

Description

technical field [0001] The invention relates to the preparation of genistein derivatives with beta-butyrylcholinesterase inhibitory effect, nerve cell protection effect, anti-inflammatory effect and long-term enhancement effect on the hippocampus to prevent or treat learning and memory impairment and neurodegeneration application in disease medicine. It belongs to the field of medical technology. technical background [0002] Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized clinically by behavioral, cognitive and memory dysfunction, and its characteristic pathological changes are: neuron loss, neuron fiber tangle ( neurofibrillary tangles (NFTs), senile plaques (SPs). The incidence of AD in people aged 65-74 is about 3%, the incidence rate can rise to 19% in people aged 75-84, and the incidence rate of AD in people over 84 years old can be as high as 47%. AD is the fourth major killer of the elderly after cardiovascular diseas...

Claims

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Application Information

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IPC IPC(8): A61K31/453A61P25/28A61P25/16A61P25/14A61P37/02A61P25/00
CPCA61K31/453
Inventor 刘艾林吴松杜冠华王冬梅方坚松周围连雯雯庞晓丛
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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