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Application of compound with flavone skeleton structure as Parkinsonism treating medicine

A Parkinson's disease and skeleton structure technology, applied in the field of medicine, can solve problems such as differences in substrate affinity, and achieve high inhibitory activity and high safety effects

Inactive Publication Date: 2012-10-31
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The two forms of COMT enzymes are almost identical in amino acid sequence, but show a large difference in the affinity with the substrate

Method used

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  • Application of compound with flavone skeleton structure as Parkinsonism treating medicine
  • Application of compound with flavone skeleton structure as Parkinsonism treating medicine
  • Application of compound with flavone skeleton structure as Parkinsonism treating medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Embodiment 1. Flavonoid catechol series compound is to the inhibitory activity determination of COMT enzyme

[0020] Using the methylation reaction of protocatechuic acid as a probe reaction, the IC of COMT enzyme inhibition by catechol series compounds was determined by means of human liver cell plasma in vitro incubation system 50 , the specific experimental procedure is as follows:

[0021] (1) Add 5mM MgCl to 200 microliters of in vitro metabolic reaction system 2 , 2mM dithiothreitol, 0.2mM S-adenosylmethionine, human liver cell plasma protein concentration is 1mg / ml, inhibitor final concentration range is 0.01μM-1μM, pre-incubated at 37°C for 3 minutes;

[0022] (2) Add the substrate (final concentration 15uM) to the reaction system to initiate the reaction; after reacting at 37°C for 30 minutes, add 200 μl of acetonitrile and shake vigorously to terminate the reaction;

[0023] (3) Using a high-speed refrigerated centrifuge, under the condition of 20,000×g, cen...

Embodiment 2

[0027] Example 2. Evaluation of metabolic activation of flavonoid catechol series compounds

[0028] In the human liver microsome incubation system with cofactor NADPH or its production system, add each flavonoid catechol series compound (final concentration: 100μM) and reduced glutathione (final concentration: 1000μM), 37℃ After incubation for 120 minutes, the reaction was terminated with an equal volume of acetonitrile, the protein was removed by centrifugation, and the adduct was detected by AB Qtrap5500 to detect whether an active adduct was captured. The results are shown in Table 2.

[0029] Table 2

[0030]

[0031] It can be seen that only the marketed drug tolcapone can produce active adducts, while no active adducts have been detected in flavonoid catechol series compounds. The results suggest that this type of compound will not produce active intermediates through metabolic activation, and will not form toxic adducts with biological macromolecules, so it will n...

Embodiment 3

[0032] Example 3. The overall pharmacokinetic study of scutellarein combined with L-dopa

[0033] Select 18 Wistar rats, half male and half male, and randomly divide them into 3 groups according to body weight (180-220g), 6 rats / group carry out the overall pharmacokinetic study of oral administration of L-dopa alone and simultaneous oral administration of scutellarein and L-dopa , and compared with the effect of the positive control (tolcapone) on the pharmacokinetics of L-dopa. About 0.5ml of rat plasma samples were collected before administration and at 5, 10, 15, 30, 60, 120, 180, and 240 minutes after administration, and placed in pre-heparinized 1.5ml pointed-bottomed brown centrifuge tubes , after centrifugation at 4000×g for 10 minutes, separate the plasma, add an equal volume of methanol to precipitate protein and centrifuge at high speed (20,000×g), remove the supernatant and store it in a -80°C refrigerator for testing. UFLC-ESI-MS was used to measure the blood conc...

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Abstract

The invention relates to application of a compound with a flavone skeleton structure as a Parkinsonism treating medicine. The compound with a flavone skeleton structure is an inhibitor for the catechol methylation transferase; and the compound specifically comprises radix scutellariae, scutellarein and structure derivatives of radix scutellariae and scutellarein, and can be used as a synergist of the Parkinsonism treating medicine levodopa. In-vitro activity test indicates that IC50 of the compound in inhibiting catechol methylation transferase can reach nanomole level, wherein the COMT(Catechol O Methyl Transferase) inhibition activity of scutellarein and the derivatives of scutellarein is superior to that of medicine tolcapone on the market. The rat overall pharmacokinetic study shows that by the joint application of scutellarein and levodopa, the blood concentration of levodopa can be obviously increased. Moreover, the compound does not generate active intermediate through metabolism activation or form toxic adduct together with biological macromolecules, thus the hepatotoxicity and nephrotoxicity caused by metabolism activation are avoided, and the compound has good prospect of patent medicine.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to the application of a compound with a flavonoid skeleton structure as a drug for treating Parkinson's disease. Background technique [0002] Parkinson's disease (PD) is a chronic degenerative disorder of the central nervous system caused by insufficient dopamine in the brain. After the illness, the patient's motor function and language ability were severely damaged, accompanied by pain, limb stiffness, tremor and other symptoms, which seriously reduced the patient's quality of life. The incidence of the disease is as high as 1.6%, and the risk of the disease increases with age [Neurology.2000;54:S24-7]. It is estimated that China is the country with the largest number of PD patients in the world, with 1.7 million patients [Lancet 2005;365:595-7]. With the advent of an aging society, the medical, family, and social problems brought about by PD have become more extens...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61K31/7048A61K45/00A61P25/16A61K31/198
Inventor 杨凌葛广波孙晓宇夏杨柳邹超洪沫
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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