CN108143734A - The application of amodiaquine and its pharmaceutically acceptable salt in the drug for treating Alzheimer disease is prepared - Google Patents
The application of amodiaquine and its pharmaceutically acceptable salt in the drug for treating Alzheimer disease is prepared Download PDFInfo
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- CN108143734A CN108143734A CN201810133662.4A CN201810133662A CN108143734A CN 108143734 A CN108143734 A CN 108143734A CN 201810133662 A CN201810133662 A CN 201810133662A CN 108143734 A CN108143734 A CN 108143734A
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- amodiaquine
- pharmaceutically acceptable
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- acceptable salt
- disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
Abstract
The invention discloses the application of amodiaquine and its pharmaceutically acceptable salt in the application in preparing the drug for treating Alzheimer disease and in being used to prepare protection neuron and/or inhibiting A β generations and/or inhibit the drug of the relevant neurodegenerative disease of Tau protein phosphorylations (including Parkinson's disease).The present invention is shown by lot of experiments; amodiaquine and its pharmaceutically acceptable salt, which have, significantly protects neural vehicles cells SH SY5Y cells and primary neuron to be damaged from STZ; inhibit the generation of A β in CHO APP cells, while can significantly inhibit the phosphorylation level of Tau albumen in primary neuronal cell.The present invention clinical indication new for exploitation amodiaquine plays an important role.
Description
Technical field
The present invention relates to medicinal application fields, and in particular to amodiaquine and its pharmaceutical composition prepare for treat Ah
Application in the drug of Alzheimer's disease, more particularly it relates to amodiaquine and its pharmaceutically acceptable salt or its
Pharmaceutical composition there is protection neuron and/or increase A β remove and/or inhibit Tau protein phosphorylations and be used to prepare treatment Ah
Application in the drug of the neurodegenerative diseases such as Alzheimer's disease.
Background technology
Alzheimer disease (Alzheimer's Disease, AD) is a kind of progressive neurodegenerative disease, is gathered with A β
The outer Amyloid deposition of nerve caused by collection, neurofibrillary tangles and neuron are thin caused by Protein tau Hyperphosphorylationof
Born of the same parents' apoptosis etc. is its outstanding feature.AD has height age-dependent, and with age, the incidence of AD also can be carried drastically
Height ends the whole world in 2011 and has had more than 30,000,000 populations with dementia, and with population in the world aging, and annual AD suffers from
Person's number is growing at top speed.China has been enter into aged society at present, and AD, which also becomes one, causes life of elderly person quality to decline simultaneously
Lead to dead major reason.At present, clinically the drug for the treatment of AD can only slow down the illness of patient, can not block AD's
Process, therefore have urgent demand to the discovery that can block the novel anti-AD drugs of AD pathogenesis.With research into
Exhibition, the pathogenesis of AD just peep clue, and patients with Alzheimer disease postmortem shows that apparent atrophy, brain occurs in its brain tissue
There are dead extensively, the lesions such as visible apparent senile plaque, neurofibrillary tangles at these positions in cell.Therefore, AD at present
Pathogenesis mainly propose three kinds of viewpoints：The irreversible apoptosis of neuron, amyloid beta (A β) hypothesis and Protein tau are false
It says, current research thinks that the anti-AD drugs for this three kinds of viewpoints may have the function of to block AD pathogenesis.
The extensive death of neuron is most apparent pathological characters in AD patient's brain, and the irreversible apoptosis of neuron is to cause god
Through (Robert M.Friedlander, M.D.Apoptosis and Caspases in the main reason for first death
Neurodegenerative Diseases.N Engl J Med 2003；348:1365-1375).A β mistakes in AD patient's brain
Amount is expressed and its toxic effect, neurofibrillary tangles, oxide damage, presenilin gene is mutated, calcium ion sensing needle is unbalance etc.
Factors finally can all lead to irreversible apoptosis (the Carl W.Cotman Aileen J.Anderson.A of neuron
potential role for apoptosis in neurodegeneration and Alzheimer's
Disease.Molecular Neurobiology, Volume 10,1995.), thus think can by antagonism Neuron Apoptosis with
Play the therapeutic effect of anti-AD.
Amyloid beta (A β) deduction thinks that aβ protein is one of main component of senile plaque, by amyloid precusor protein
(APP) generation is sheared successively through beta-secretase and gamma-secretase, it excessively increases in cerebral tissue causes nervous system to generate
Oxidative stress, inflammatory reaction etc. eventually lead to Neuron Apoptosis and the generation of AD.Therefore the generation by inhibiting A β is generally believed
Or promote the removing of A β that can effectively prevent or treat AD to reduce the content of A β in whole brain, and this is also current anti-AD
One of main R＆D direction of newtype drug (Yamin G, Ono K, Inayathullah M, Teplow D B.Amyloid
beta-protein assembly as a therapeutic target of Alzheimer’s disease.Current
Pharmaceutical Design,2008,14:3231-3246；Kurz A,Perneczky R.Amyloid clearance
as a treatment target against Alzheimer’s disease.Journal of Alzheimer's
disease,2011,24[Suppl 2]:61-73.)。
Tau albumen hypothesis think that the neurofibrillary tangles formed by Tau protein hyperphosphorylations finally also result in god
It transmits and damages through first mediator, apoptosis of neuron etc. eventually leads to AD.Tau albumen is a kind of microtubule associated protein, can be with
Tubulin is promoted to be assembled into micro-pipe and maintains the structure of micro-pipe, the wide expression in nerve fiber, and in AD patient's brain tissue
By different Hyperphosphorylationof (D.N.Drechsel, A.A.Hyman, M.H.Cobb, M.W.Kirschner.Modulation of
the dynamic instability of tubulin assembly by the microtubule-associated
protein tau.Molecular biology of the cell,1992,3,:1141).Under normal circumstances, Tau albumen
Phosphorylation and dephosphorylation are in dynamic equilibrium, but under abnormal conditions, and Protein tau meeting peroxophosphoric acid loses maintenance micro-tubular structure
Function, cause the diseases such as AD, Parkinson's syndrome.
Amodiaquine, clinic are usually used in the treatment of malaria, act on erythrocyte stage.Neuron is protected for it at present
And/or inhibit A β generations and/or inhibit Tau protein phosphorylations, so as to play anti-Alzheimer disease (Alzheimer ' s
Disease, AD) effect have not been reported.The present invention is further discovered that amodiaquine has protection neuron and/or inhibits A β lifes
Into and/or inhibit the effects of Tau protein phosphorylations, therefore the present invention be further discovered that it to new indication treat it is potential should
With.
Invention content
It is an object of the present invention to provide the new medical applications of amodiaquine and its pharmaceutically acceptable salt, i.e., its
Application in the drug for treating Alzheimer disease is prepared.
In the application, amodiaquine and its pharmaceutically acceptable salt can protect neuron and/or inhibit Tau eggs
White phosphorylation and/or rush inhibits A β generations.The pharmaceutically acceptable salt, including inorganic acid salt, acylate, such as apple
Tartaric acid salt, succinate, hydrochloride etc..
It is a further object to provide amodiaquines and its pharmaceutically acceptable salt to prepare treatment and nerve
Application in the drug of member damage, A β generations and/or the relevant neurodegenerative disease of Tau protein phosphorylations.
The neure damage and/or A β generations and/or the relevant neurodegenerative disease of Tau protein phosphorylations include
But it is not limited to Parkinson's disease etc..
It is a further object of the present invention to provide the pharmaceutical compositions comprising amodiaquine or its pharmaceutically acceptable salt to exist
The application in the drug for treating Alzheimer disease is prepared, described pharmaceutical composition includes amodiaquine or it pharmaceutically may be used
The salt of receiving and pharmaceutically acceptable various auxiliary materials.
The invention also discloses the pharmaceutical compositions to prepare and neure damage and/or A β generations and/or Tau albumen phosphorus
The application being acidified in the drug of relevant neurodegenerative disease.
Amodiaquine of the present invention, molecular formula:C20H22N3OCl, molecular weight:355.86 chemical formula is：
Advantageous effect：
The present invention is screened by many experiments, it was found that the new mechanism of action and drug effect of amodiaquine have patron saint
Through first effect, and it can or inhibit the phosphorylation of Tau albumen, while can inhibit the effect of A β generations.Therefore, amodiaquine can be used
In prepare treatment Alzheimer disease and with neuronal damage and/or the drug of the relevant disease of A β and/or Tau albumen.
Description of the drawings
Fig. 1 can protect SH-SY5Y cells and primary neuron from streptozotocin for amodiaquine
The block diagram of the damaging action of (Streptozocin, STZ).* * represent P<0.001.One-way analysis of variance.
Fig. 2 amodiaquines can inhibit the block diagram of the nucleus formation of A β in CHO-APP cells.* represents P<0.005.It is single
Analysis of variance.
Fig. 3 amodiaquines can inhibit the block diagram of primary neuron Tau protein phosphorylation horizontal forces.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated, but these embodiments should not be construed as limiting this hair
It is bright.
Test example 1：Amodiaquine (Amodiaquine) protects the experiment of SH-SY5Y cells and primary neuron.
The present invention detects amodiaquine in SH-SY5Y cells and primary neuron and cell caused by streptozotocin is damaged
The protective effect of wound, experiment show that amodiaquine has the function of significantly to protect neuron.
1st, experimental principle
This experiment is based on streptozotocin (Streptozocin, STZ) and is widely used as internal and external oxidative stress mediation
Apoptosis, therefore give SH-SY5Y cells and primary neuron STZ processing to simulate the neuron under AD states in vitro, the present invention
The amodiaquine of STZ and various concentration is added in SH-SY5Y cells and primary neuronal culture liquid and is incubated certain time jointly,
Then it measures cell viability by MTT detection methods to change, protective effect of the amodiaquine to SH-SY5Y cells is evaluated with this
(Tarek KASHOUR,Teralee BURTON,Alexander DIBROV,Francis M.AMARA.Late Simian
virus 40transcription factor is a target of the phosphoinositide 3-kinase/Akt
pathway in anti-apoptotic Alzheimer’s amyloid precursor protein
signaling.Biochem.J.(2003)370,1063±1075)。
The neuroprotection of amodiaquine is evaluated in this experiment by MTT detection methods, and principle is：In living cells mitochondria
Succinate dehydrogenase exogenous MTT can be made to be reduced to the bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble and be deposited on thin
In born of the same parents, and dead cell is without this function.Dimethyl sulfoxide (DMSO) (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, be existed with enzyme-linked immunosorbent assay instrument
Its absorbance value is measured at 490nm wavelength, can reflect living cells quantity indirectly.In the range of certain cell number, MTT crystallizes to be formed
Amount it is directly proportional to cell number.
2nd, experiment material and method
1) STZ for inducing cell damage is purchased from Sigma companies, and cell culture reagent is purchased from Gibco companies, SH-
SY5Y cell deriveds are in ATCC.Primary neuron is derived from C57BL6 mouse cortexs.
2) MTT is tested：SH-SY5Y cells and primary neuron are respectively with 105A/hole and 6*105Concentration with 100ul
It being inoculated in 96 orifice plates, the amodiaquine for giving 0.8mM STZ and various concentration after cell pellet overnight is adherent is incubated 24 hours, after
Removing original culture medium, addition MTT is incubated 4 hours in 37 DEG C per hole, the final concentration of 0.5mg/ml of MTT.It finally removes original in hole
100ul DMSO are added in after culture medium, to dissolve first a ceremonial jade-ladle, used in libation and read light absorption value at 490nm wavelength in microplate reader.
3rd, experimental result
As a result as shown in a in Fig. 1, amodiaquine can concentration dependent improve SH-SY5Y cells in cell caused by STZ
Vigor decline and, as shown in b in Fig. 1, amodiaquine can concentration dependent improve primary neuron in caused by STZ cell live
Power declines, the results showed that amodiaquine has the neuroprotection of apparent concentration dependent.
Test example 2：Amodiaquine (Amodiaquine) inhibits A β generations.
For the present invention to detect the influence that amodiaquine generates A β in CHO-APP cells, experiment shows that amodiaquine has
Play the role of that A β is significantly inhibited to generate.
1st, experimental principle
Chinese hamster ovary celI of this experiment based on swedish mutant type people source APP can shear approach by APP and generate endogenous A β.
The amodiaquine of various concentration is added in CHO-APP cell culture fluids and is incubated certain time jointly by the present invention, then takes upper strata
Cell culture fluid detection wherein A β contents, while clean cell and crack and survey its protein concentration to eliminate cell density different band
Influence, the reduction of A β contents in final culture medium shows that amodiaquine can inhibit A β generations.[CJ Phiel.GSK-3α
regulates production of Alzheimer's disease amyloid-βpeptides,Nature,volume
423,pages 435–439(22May 2003)]。
By ELISA method detection, principle is for A β generations of the present invention：The endogenous A β generated in CHO-APP cells pass through
In exocytosis secretion to culture medium, after by culture medium move into be coupled have A β antibody 96 orifice plate of white clear be incubated, then add in A
Another site antibodies of β are carried out at the same time incubation, and combination principle is identified by antigen and antibody specific, and A β and its antibody is special simultaneously
The opposite sex is adsorbed on 96 orifice plates；Then with the secondary antibody and its chromogenic substrate for being coupled horseradish peroxidase
(Tetramethylbenzidine, TMB) is incubated, and the coloured product depth of generation is directly proportional to A β contents, respectively bioassay standard
The absorbance value (OD450) of pipe and sample tube calculates the content of A β.
2nd, experiment material and method
1)Aβ40Assay kit is purchased from invitrogen companies, and cell culture reagent is purchased from Gibco companies, CHO-APP
Cell derived is in ATCC.
2) CHO-APP cells A β generations experiment：After CHO-APP cell culture to 70% density, add in various concentration Ah
Quinoline (20,10,5,0 μM) is not incubated 24 hours jointly, then collects upper strata culture medium, and cell is cleaned 3 times with PBS, is added in thin
Cellular lysate liquid (50mM Tris, 1%SDS) cracks 15 minutes in 37 DEG C, and then 12,000g centrifugations 15 minutes, A β lead in culture medium
The method for crossing ELISA measures.
3) cell culture medium of collection is detected according to kit institute providing method.It i.e. at room temperature will be after dilution
Cell culture medium, A β40Antibody and coupling A β4096 orifice plates of another antibody are incubated 3 hours jointly, are then carried in kit
The rinsing liquid of confession carries out board-washing 4 times, and the secondary antibody that adding coupling has horseradish peroxidase is incubated 30 minutes at room temperature, then with floating
Then washing lotion board-washing four times adds in developing solution in incubation at room temperature 30 minutes, is eventually adding stopping of reaction liquid.With Tecan microplate reader
OD values are read at 450nm.
3rd, experimental result
The results are shown in Figure 2, and what amodiaquine was capable of concentration dependent reduces the intracellular A β of CHO-APP40Content, table
Bright amodiaquine has the function of the inhibition A β generations of apparent concentration dependent.
Test example 3：Amodiaquine (Amodiaquine) inhibits the phosphorylation of Tau albumen.
Neurofibrillary tangles are one of pathogenic factors important in AD pathology caused by Tau protein hyperphosphorylations.
Therefore the present invention is tested by Western blot and further studies tune of the compound amodiaquine to Tau protein phosphorylations level
Section acts on.The result shows that in primary neuronal cell, amodiaquine can significantly decrease Protein tau 396,231 and
199 phosphorylation levels.
1st, experimental principle
Western blot are tested:There are wide expressions in nervous system for Tau albumen, equally have in primary neuron
There is expression, phosphorylation level height is assembled into micro-pipe and the important work of structure for maintaining micro-pipe by tubulin is directly influenced
With, therefore Tau 6 phospho-ABs of protein 39 are utilized, 231 antibody and 199 antibody come after directly detecting cell cracking
The phosphorylation level of Protein tau, glyceraldehyde 3-phosphate dehydro-genase (GAPDH) is as control test compound to the phosphorylation of Tau
Influence.
2nd, experiment material and method
1) cell culture reagent is purchased from Gbico companies, and primary neuron is derived from C57BL/6 mouse Cerebral cortex, Tau albumen
396 phospho-ABs, 1 phospho-AB of Tau protein 23s, 9 phospho-ABs of Tau protein 19s, GAPDH antibody are purchased from
Cell signaling companies.
2) Western blot test major parameter：Primary antibody：p396-tau(1:1000, Cell signaling companies),
p231-tau(1:1000, Cell signaling companies), p199-tau (1:1000, Cell signaling companies), Tau
(1:1000, Cell signaling companies), GAPDH (1:10,000, Cell signaling)；Secondary antibody：Rabbit-anti (anti-
Rabbit)(1:5,000, Jackson companies), mouse resists (anti-mouse) (1:10,000, AbCam Co., Ltds).
3) experimental method：In cell experiment, primary neuron is with 6*105Concentration be incubated in six orifice plates, wait to cultivate
The amodiaquine (0,2,5,10 μM) of various concentration is added in after to the 9th day, cultivates 24 hours, then draws culture solution, and with
PBS is cleaned 3 times, and subsequent cell receives sample buffer solution (25%SDS, 62.5mM Tris, 25% glycerine, 0.1% bromine with SDS-PAGE
It is fragrant blue, pH6.8) it is collected in the EP pipes of 1.5mL, heat 15 minutes in 98 DEG C, then in 4 DEG C with 10000 revs/min,
Centrifugation 10 minutes.Supernatant carries out SDS-PAGE electrophoresis, is then walked around film 90 minutes using semidry method electricity, then by film in TBST envelopes
Close closing 30 minutes in liquid (TBS, 0.5% polysorbas20,5% skimmed milk power).By the film after closing with being incubated corresponding to 4 DEG C
Night.Film is washed with TBST buffer solutions (TBS, 0.5% polysorbas20) 3 times (every time 15 minutes) within second day, then carry out incubation 2 with secondary antibody
Hour.It is then similary that film is washed 3 times (every time 15 minutes) using TBST buffer solutions.Finally with horseradish peroxidase (HRP) substrate
It is incubated 5 minutes, signal is then collected using 4200 luminescence imaging systems of Tanon.
3rd, experimental result：
The results are shown in Figure 3, and compared with compareing DMSO processing groups, amodiaquine can be with the inhibition Tau eggs of concentration dependent
The white phosphorylation of 396,231 and 199, shows that amodiaquine can significantly inhibit the phosphorylation of Tau albumen.
The technical concepts and features of embodiment of above only to illustrate the invention, its object is to allow be familiar with technique
People understands the content of present invention and is implemented, and it is not intended to limit the scope of the present invention, all real according to spirit of the invention
The equivalent change or modification that matter is done should all cover within the scope of the present invention.
Claims (7)
1. the application of amodiaquine and its pharmaceutically acceptable salt in the drug for treating Alzheimer disease is prepared.
2. application according to claim 1, which is characterized in that amodiaquine and its pharmaceutically acceptable salt can protected
It protects neuron and/or inhibits A β generations and/or inhibit Tau protein phosphorylations.
3. amodiaquine and its pharmaceutically acceptable salt are being prepared for treatment and neure damage, A β generations and/or Tau eggs
White phosphorus is acidified the application in the drug of relevant neurodegenerative disease.
4. application according to claim 3, which is characterized in that the neurodegenerative disease includes Parkinson's disease.
5. application of a kind of pharmaceutical composition in the drug for treating Alzheimer disease is prepared, which is characterized in that described
Pharmaceutical composition includes amodiaquine or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
6. the pharmaceutical composition containing amodiaquine or its pharmaceutically acceptable salt is being prepared for treatment and neure damage
And/or the application in the drug of A β generations and/or the relevant neurodegenerative disease of Tau protein phosphorylations.
7. application according to claim 6, the neurodegenerative disease includes Parkinson's disease.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110623960A (en) * | 2018-06-22 | 2019-12-31 | 成都山权江生物科技有限公司 | Application of small molecular compound in preparation of medicine for inhibiting Tau protein expression |
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| US4806537A (en) * | 1987-04-16 | 1989-02-21 | City Of Hope | Use of amodiaquin and related compounds in treatment of nervous system degeneration |
| CN1819822A (en) * | 2003-01-27 | 2006-08-16 | 贝勒医学院 | Compositions containing substituted quinolines and substituted diphenyl sulfones and methods of use |
| JP2014196269A (en) * | 2013-03-29 | 2014-10-16 | 公益財団法人東京都医学総合研究所 | Pharmaceutical composition for therapy or prevention of neurodegenerative disease, comprising amodiaquine |
| CN106687626A (en) * | 2014-04-30 | 2017-05-17 | 宇凤·简·曾 | Use of known compounds as d-amino acid oxidase inhibitors |
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2018
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| US4806537A (en) * | 1987-04-16 | 1989-02-21 | City Of Hope | Use of amodiaquin and related compounds in treatment of nervous system degeneration |
| CN1819822A (en) * | 2003-01-27 | 2006-08-16 | 贝勒医学院 | Compositions containing substituted quinolines and substituted diphenyl sulfones and methods of use |
| JP2014196269A (en) * | 2013-03-29 | 2014-10-16 | 公益財団法人東京都医学総合研究所 | Pharmaceutical composition for therapy or prevention of neurodegenerative disease, comprising amodiaquine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110623960A (en) * | 2018-06-22 | 2019-12-31 | 成都山权江生物科技有限公司 | Application of small molecular compound in preparation of medicine for inhibiting Tau protein expression |
| CN110623960B (en) * | 2018-06-22 | 2022-08-19 | 成都山权江生物科技有限公司 | Application of small molecular compound in preparation of medicine for treating Alzheimer disease |
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