CN108926565A - The application of 6 small molecule activators of serotonin receptor subtype and antagonist in prevention and treatment Alzheimer's disease - Google Patents
The application of 6 small molecule activators of serotonin receptor subtype and antagonist in prevention and treatment Alzheimer's disease Download PDFInfo
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- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004577 thatch Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention belongs to life science fields, and in particular to the antagonist of serotonin receptor subtype 6 is preparing the purposes in amyloid A beta inhibitor.First passage elisa of the present invention reduces amyloid A β generation experiments have shown that the agonist and antagonist of targeting serotonin receptor subtype 6 can be fastened in the nerve cell of people, due in patient's cerebrospinal fluid, change of the concentration variation of A β earlier than Protein tau level, amyloid beta deposition is also earlier than the appearance of clinical symptoms, in view of from A β small peptide gather patch formation be A β concentration dependant, find reduce A β concentration method for treatment for it is very important.Therefore, the activator and antagonist for targeting serotonin receptor subtype 6, which reduce A β generation and the announcement of related mechanism, to provide the directive significance of clinical trial for the treatment of Alzheimer's disease and further medicament research and development.
Description
Technical field
The invention belongs to life science fields, and in particular to the antagonist of serotonin receptor subtype 6 (HTR6) exists
Prepare the purposes in amyloid protein (A β) inhibitor.
Background technique
Alzheimer disease (Alzheimer disease, AD), is called senile dementia, is a kind of central nervous system
Degenerative disease, insidious onset, the course of disease are in slow progressive, are senile dementia one of the most common type types.It is risen according in crowd
The difference of source situation, AD can be divided into sporadic and two class of familial form, and wherein familial inheritance type case accounts for about 5%, to this kind of disease
Example researches show that on APP, PSEN1 and PSEN2 gene mutation it is directly related with the morbidity of AD, other overwhelming majority distribute disease
The pathogenesis of example is unclear, can be divided into four-stage according to progression of the disease, first stage is often incorrectly attributed to always
Change or pressure, generally have the time up to 8 years apart from exact pathological diagnosis, are mainly shown as that mild cognitive is difficult and adjoint
There is short term memory loss, influences whether more complex number of storage tanks produced per day.Early stage Alzheimer's disease shows as forgetting household
Or the name of friend, usually these changes can only be found by close friend or relative.Mid-term Alzheimer's disease is to remembeing
Situations such as there is bigger difficulty in the information recognized recently, and adjoint chaotic problem of sleeping often is got lost.Advanced stage Ah
It is poor that elaborative faculty occurs in your thatch Alzheimer disease, repeats same dialogue and with anxiety, and gradually physical function is lost, and life is not
It can take care of oneself, eventually lead to death.According to the World Health Organization (WHO) and ADI (Alzheimer Disease International)
Statistics in 2015, there are about 45,000,000 in global 900,000,000 ageds to suffer from AD, doubles after this number is 20 years estimated,
The year two thousand fifty reaches 1.3 hundred million, at present about 604,000,000,000 dollars of cost burden of the senile dementia in the whole world, even if AD is also to pass through in developed country
Therefore one of the disease of most expensive in Ji discloses the pathomechanism of AD and the research for filtering out novel low-toxicity high potency drugs is compeled
The eyebrows and eyelashes.
The characteristic pathology of patient AD changes into amyloid beta and deposits the extracellular senile plaque to be formed and Protein tau mistake
Spend neurofibrillary tangles and the adjoint glial cells hyperplasia etc. of neuron loss in the nerve cell that phosphorylation is formed.About
The pathogenesis of AD has the heredity of a series of complex and environmental factor to participate so far still without final conclusion, and opinions vary.And it is current
Relatively broad receiving is amyloid beta hypothesis.The hypothesis is established at Presbyophrenia (early-onset AD) point
On sub horizontal Research foundation, propose that APP, PS1 or PS2 gene mutation will lead to the abnormal of intracellular aβ protein and increases, A β is more
Dimerization forms patch, and A β oligomer finally makes neuron axon gap be damaged by a series of cascade reactions, at this
Process No microglial and star spongiocyte can be activated.Impaired neuronal cell can change ion permeability (calcium from
Sub- level increases substantially in cytoplasm) while oxidative damage can be caused, change kinase phosphorylation enzymatic activity and forms neural fibre
It ties up silk to tangle, eventually leads to cognitive disorder.Therefore, it may be most promising treatment that interference A β, which forms and prevent it from generating deposition,
AD method, and explain the main theoretical basis of the sporadic AD cause of disease.
Following side is divided into for the therapeutic strategy of Alzheimer's disease and drug at present in view of complicated pathogenesis
Face：
1) the relevant therapy approach of cholinergic transmitter, anticholinesterase (AChE I) are most common cholinergic
Mediator related drugs, including Aricept (donepezil, donepezil), Exelon (rivastigmine, benefit this quick) and
The work of their energy Selective long-range DEPT Cerebral cortex and hippocampus etc. positions acetylcholines of Razadyne (galantamine, galanthamine)
With, hence it is evident that improve cognitive function, the activity of daily living of patient, alleviates coincident with severity degree of condition.
2) brain metabolism improving.
3) the anti-AD effect of anti-inflammatory treatment, non-steroidal anti-inflammatory drugs may pass through the paraplasm shadow of inhibition microglia
Ring the process of AD.
4) anti-oxidant free radical resisting, such as melatonin, gadol extract, curcumin have confrontation cellular oxidation damage
Wound reduces intracellular calcium concentration and reduces the effect of nerve cell death, by reducing the level of biological interior free yl,
It protects cell and tissue to attack from free radical, the anti-amyloid that occurs of oxidativestress damage is avoided to pass through the conjunction for preventing A β
At and precipitating, regression and the apoptosis of neuron can be improved.
5) β-amyloid proteins deposition medicine etc., since current senile dementia Etiologic Mechanism does not illustrate also completely, big portion are interfered
The drug of anti-senile dementia is divided to be used only to improve symptom and delay progression of the disease.
In consideration of it, further disclosing specificity adjusts the novel molecular mechanism that A β is generated, becomes and carry out anti-AD class medicine at present
Object research and development and disease treatment critical issue urgently to be resolved.
G- G-protein linked receptor (G-protein coupled receptor, GPCR) is the most cell membrane of known number
Surface receptor family, there are about 1000 members.Its main feature is that having 7 transmembrane structures, N-terminal is extracellular, and C-terminal is in cell
It is interior.GPCR can signal stimulus outside permissive cell, conduction regulates and controls downstream signaling pathway, and then for all multiple to intracellular
Physiology, pathologic process is wanted to play regulatory function.Rear GPCR is activated in conjunction with agonist, and occurred conformation changes, and activates G egg
It is white, change the level of intracellular second messenger (such as cAMP, Ca2+ etc.), and then mediating effect+6 protein active and function；With this
Meanwhile receptor phosphorylation can be raised β-arrestin to receptor, cause receptor from cell membrane table by G- G-protein linked receptor kinases
Face is transported into the cell, to terminate receptors signal transduction, some GPCR can also participate in neuronal synapse caused by adjusting A β
Changes of function plays neuroprotection or neurotoxic effect, and then influences AD Development process.Serotonin be serotonin by
The endogenous ligands of body.Serotonin receptor (serotonin receptors, HTRs) is broadly divided into 7 hypotypes, except HTR3 be with
Outside the ion channel of body gate, remaining 6 kinds of hypotypes are the A class g protein coupled receptor of seven cross-films.HTR6 and other hypotypes
HTR sequence homology it is lower, almost only expressed in central nervous system.Compared with ACh neuron, HTR6 exists
Relative expression is higher in GABA serotonergic neuron and glutaminergic neurons.
Summary of the invention
In order to overcome the problems of in the prior art, the purpose of the present invention is to provide serotonin receptor subtypes 6
(HTR6) antagonist is preparing the purposes in amyloid protein (A β) inhibitor.
To achieve the goals above and other related purposes, the present invention adopt the following technical scheme that：
The first aspect of the present invention, the antagonist for providing serotonin receptor subtype 6 (HTR6) are preparing amyloid protein
Purposes in (A β) inhibitor.
Preferably, the antagonist of the serotonin receptor subtype 6 (HTR6) is able to suppress amyloid protein (A β) generation
Or reduce amyloid protein (A β) level.
Preferably, the antagonist of the serotonin receptor subtype 6 (HTR6) is able to suppress amyloid egg in nerve cell
It is horizontal that white (A β) generates or reduce amyloid protein (A β) in nerve cell.
As cited in some embodiments of the present invention, the antagonist energy of the serotonin receptor subtype 6 (HTR6)
Amyloid protein (A β) in SK-N-SH cell is enough inhibited to generate or reduce amyloid protein (A β) level in SK-N-SH cell.
Preferably, the antagonist Yu serotonin receptor subtype 6 (HTR6) of the serotonin receptor subtype 6 (HTR6)
There is stronger affinity, and without intrinsic activity, effect is not generated, but can block excitomotor and serotonin receptor subtype 6
(HTR6) it combines, thus fights or cancel the effect of excitomotor, be divided into competitive antagonist and noncompetitive antaganist.
Preferably, the antagonist of the serotonin receptor subtype 6 (HTR6) be selected from SB258585hydrochloride,
SB271046 hydrochloride、Intepirdine RVT-101、Idalopirdine。
The structural formula of the SB258585hydrochloride is shown in formula I：
Molecular formula is C18H22IN3O3S.HCl, molecular weight 523.82, CAS No:1216468-02-8,
Chemical name is：
4-Iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]
benzenesulfonamide hydrochloride。
The structural formula of the SB271046hydrochloride is as shown in Formula II：
Molecular formula is C20H22ClN3O3S2.HCl, molecular weight 488.45, CAS No:209481-24-3,
Chemical name is：
5-Chloro-N-[4-methoxy-3-(1-piperazinyl)phenyl]-3-methyl-benzo[b]
thiophen-2-sulfonamide hydrochloride。
The structural formula of the Intepirdine RVT-101 is as shown in formula III：
Molecular formula is C19H19N3O2S, molecular weight 353.44, CAS No:607742-69-8,
Chemical name is：3-Phenylsulfonyl-8-(piperazin-1-yl)quinoline.
The structural formula of the Idalopirdine as shown in formula IV,
Molecular formula is：C20H19F5N2O, molecular weight 398.141754D,
ChemSpider ID：19878969.
Preferably, the purposes further includes any one or multinomial of following characteristics：
(1) SB258585hydrochloride inhibits amyloid A β by acting on serotonin receptor subtype 6
Generate or reduce amyloid A β level；
(2) SB258585hydrochloride inhibits amyloid A β to generate by reducing BACE1 secretase activity
Or reduce amyloid A β level；
(3) SB258585hydrochloride is believed by acting on the classical GPCR of the mediation of serotonin receptor subtype 6
Number access inhibits amyloid A β to generate or to reduce amyloid A β horizontal；
(4) SB258585hydrochloride is pressed down by interfering the interaction of serotonin receptor subtype 6 and CDK5
Amyloid A β processed generates or reduces amyloid A β level；
(5) β-arrestin2 that SB258585hydrochloride is mediated by acting on serotonin receptor subtype 6
To inhibit, amyloid A β is generated signal path or reduction amyloid A β is horizontal.
The second aspect of the present invention provides SB258585hydrochloride in preparing BACE1 Secretase inhibitors
Purposes.
Preferably, the SB258585hydrochloride can reduce BACE1 secretase shear active.
The third aspect of the present invention provides SB258585hydrochloride in the group for preparing serotonin receptor subtype 6
Purposes in Constitutive active inhibitor.
Preferably, the SB258585hydrochloride can reduce the constitutive activity of serotonin receptor subtype 6
The cAMP of mediation is horizontal.
The fourth aspect of the present invention, the activator for providing serotonin receptor subtype 6 (HTR6) are preparing amyloid protein
Purposes in (A β) inhibitor.
Preferably, the activator of the serotonin receptor subtype 6 (HTR6) is able to suppress amyloid protein (A β) generation
Or reduce amyloid protein (A β) level.
Preferably, the activator of the serotonin receptor subtype 6 (HTR6) is able to suppress amyloid egg in nerve cell
It is horizontal that white (A β) generates or reduce amyloid protein (A β) in nerve cell.
As cited in some embodiments of the present invention, the activator energy of the serotonin receptor subtype 6 (HTR6)
Amyloid protein (A β) in SK-N-SH cell is enough inhibited to generate or reduce amyloid protein (A β) level in SK-N-SH cell.
Preferably, the activator is selected from ST1936oxalate.
The structural formula of the ST1936oxalate is shown as a formula V：
Molecular formula is：C13H17ClN2.C2H2O4, molecular weight is
326.78 CAS No:1210-81-7,
Chemical name is：5-Chloro-3-[2-(dimethylamino)ethyl]-2-methylindole
oxalate。。
The fifth aspect of the present invention provides a kind of method for inhibiting amyloid A β, including step：By serotonin by
The antagonist or activator of body hypotype 6 are applied to object.
The object can be nerve cell.Such as：SK-N-SH cell.
The antagonist of the serotonin receptor subtype 6 be selected from SB258585hydrochloride,
SB271046hydrochloride、Intepirdine RVT-101、Idalopirdine。
The activator of the serotonin receptor subtype 6 is selected from ST1936oxalate.
Compared with prior art, the present invention has the advantages that：
First passage elisa of the present invention is experiments have shown that the agonist and antagonist of targeting serotonin receptor subtype 6 all may be used
Being fastened with the nerve cell in people, which reduces amyloid A β, generates, due in patient's cerebrospinal fluid, the concentration variation of A β earlier than
The change of Protein tau level, amyloid beta deposition is also earlier than the appearance of clinical symptoms, it is contemplated that gathers patch from A β small peptide
Formation is A β concentration dependant, find reduce A β concentration method for treatment for it is very important.Therefore, five are targeted
The activator and antagonist of HT receptor subtypes 6 reduce A β generation and disclosing for related mechanism can controlling for Alzheimer's disease
It treats and further medicament research and development provides the directive significance of clinical trial.
Detailed description of the invention
Fig. 1：SK-N-SH cell Serotonin receptor different subtype expression.
Fig. 2：SB258585hydrochloride can reduce the endogenous A β of SK-N-SH and generate, SK-N-SH giving of cell
After closing object processing 24 hours, training liquid supernatant is collected, ELISA detects cell A β and generates level, * P<0.05,***P<0.005.
Fig. 3：SB258585hydrochloride reduces the effect that A β is generated and depends on serotonin receptor subtype, left figure：
SK-N-SH slow virus infected cell replaces fresh culture medium after 24 hours, divide disk to 48 orifice plates after 48 hours, give after 72 hours
10 μM of compound processing of cell are given, cells and supernatant is collected after 96 hours, ELISA detects A β and generates horizontal, right figure：Fluorescence is fixed
Poor efficiency, * * P are struck in amount pcr detection<0.01, compared with solvent control group；***P<0.005, infection targeting HTR6shRNA virus
And ligand stimulation group is given with infection Scrambled shRNA and compared with giving ligand stimulation group.
Fig. 4：SB258585hydrochloride, which is indirectly depended on, reduces BACE1 secretase shear active, * P<0.05.
Fig. 5：SB258585hydrochloride reduces the classics that part A depends on serotonin receptor subtype 6 to mediate
GPCR signal path, the cell of virus infection pGlo-20F and HTR6 are laid on white 96 orifice plates, replacement training liquid after transfection 24 hours
For the training liquid containing 2%GloSensor Reagent, 37 DEG C are incubated for 1.5 hours, and are read by Berthold 941
Luminescence background reading；Then, certain density compound is added to handle 15 minutes, again by Berthold941
Luminescence reading is read, striking low G α also a degree of can inhibit the effect * P for reducing A β and generating of antagonists to mediate
<0.05, * * * P<0.005.
Fig. 6：SB258585hydrochloride reduces the phase interaction for partly depending on 6 receptor of serotonin with CDK5
With 1) the picture left above：SK-N-SH slow virus infected cell renews fresh culture medium after 24 hours, divide disk to 48 orifice plates after 48 hours,
It gives cell 10 μM of compound processing after 72 hours, cells and supernatant is collected after 96 hours, ELISA detects A β and generates level；
2) top right plot：Poor efficiency is struck in Western blot detection；3) following figure：Addition inhibitor (Roscovitine (Seliciclib,
CYC202, selective CDK inhibitor) compound processing is added after pretreatment 45 minutes, cells and supernatant is collected after 24 hours,
ELISA detects A β and generates horizontal, * * P<0.01, compared with solvent control group；**P<0.005, infection targeting CDK5shRNA virus
And ligand stimulation group is given compared with infecting Scrambled shRNA and giving ligand stimulation group and inhibitor has been added to locate in advance
It manages and gives ligand stimulation group compared with inhibitor is not added and pre-processes and gives ligand stimulation group.
Fig. 7：SB258585hydrochloride reduces the β-that A beat portion depends on serotonin receptor subtype 6 to mediate
Arrestin2 signal path, 1) left figure：SK-N-SH slow virus infected cell renews fresh culture medium after 24 hours, after 48 hours
Divide disk to 48 orifice plates, gives cell 10 μM of compounds processing after 72 hours, cells and supernatant, ELISA inspection are collected after 96 hours
It surveys A β and generates level；2) right figure：Poor efficiency, * * P are struck in Western blot detection<0.01, compared with solvent control group；**P<
0.005, infection targeting β-arrestin2shRNA virus simultaneously gives ligand stimulation group and transfects Scrambled shRNA and give
Ligand stimulation group is compared.
Fig. 8：Other 6 antagonists of serotonin receptor subtype and activator can also reduce A β generation, * P<0.05, * * P<
0.01, * * * P<0.005.
Specific embodiment
Before further describing the specific embodiments of the present invention, it should be appreciated that protection scope of the present invention is not limited to down
State specific specific embodiment；It is also understood that term used in the embodiment of the present invention is specific specific in order to describe
Embodiment, rather than limiting the scope of protection of the present invention.The test method of actual conditions is not specified in the following example,
Usually according to normal condition, or according to condition proposed by each manufacturer.
When embodiment provides numberical range, it should be appreciated that except non-present invention is otherwise noted, two ends of each numberical range
Any one numerical value can be selected between point and two endpoints.Unless otherwise defined, the present invention used in all technologies and
Scientific term is identical as the normally understood meaning of those skilled in the art of the present technique.Except specific method, equipment used in embodiment,
Outside material, grasp and record of the invention according to those skilled in the art to the prior art can also be used and this
Any method, equipment and the material of the similar or equivalent prior art of method described in inventive embodiments, equipment, material come real
The existing present invention.
One, cell culture and plasmid construction
Cell is incubated at 37 DEG C of cell incubators containing 5% carbon dioxide, and SK-N-SH cell culture is in containing 10% tire
The MEM.F12 culture medium of cow's serum；HEK293T cell culture is in the DMEM culture medium for containing 10% fetal calf serum.Source of people has
6 plasmid of serotonin receptor subtype of HA label is organized by drug institute teacher Xie Xin and is provided, and is prepared for pentahydroxy- color with subcloning procedures
Amine receptor hypotype 6 and F20 slow virus plasmid.The building of all shRNA clones has references to the method on addgene webpage
(Addgene,http://www.addgene.org/tools/protocols/plko/)
Two, virus packet turns and infects
HEK293T is with 7.5 × 106Cell density be layered on second day in the culture dish of 10cm, turned with the method for calcium phosphate
The target plasmid of 20 μ g, the pSPAX2 packaging plasmid of 16 μ g are contaminated, the pMD2G packaging plasmid of 6 μ g renews fresh culture after 12 hours
Base.Later respectively in 48 hours and 72 hours collection viral supernatants, 1000 × g is centrifuged 5 minutes, after being filtered with 0.45- μm of filter
With the ultracentrifugation of 27,000 × g 2 hours under the conditions of 4 DEG C.Precipitating is resuspended in the PBS of 200 μ l, be divided in after dissolution-
The method of 80 DEG C of streamings measures virus titer.For striking low experiment, SK-N-SH cell is first layered on 10cm with suitable density
In culture dish or in 24 orifice plates, cell density about carries out virus infection in 50-70% after cell is 16-24 hours adherent, and 24 is small
When after change liquid, strike inefficient 72-96 hour in virus infection and interior detected by fluorescent quantitation pcr.
Three, enzyme-linked immunosorbent assay detects A β/sAPP α/sAPP β
The SK-N-SH cell for being laid on 48 orifice plates, which is given, collects training liquid supernatant after compound is handled 24 hours, with sandwich method enzyme
A/sAPP α/sAPP the β for joining immunoadsorption assay quantitative detection training liquid supernatant is horizontal.
Four, cell survival detects
Be laid on 48 orifice plates SK-N-SH cell give compound handle 24 hours after with PBS rinse 2 times after be added detection examination
Agent CellTiter-Glo Luminescent Cell Viability Assay detects cell viability.
Five, it is horizontal to detect cAMP by GloSensorTM cAMP biosensor
The cell of virus infection pGlo-20F and HTR6 are laid on white 96 orifice plates, after transfection 24 hours replacement training liquid be containing
The training liquid of 2%GloSensor Reagent, 37 DEG C are incubated for 1.5 hours, and read Luminescence by Berthold 941
Background reading；Then, certain density compound is added to handle 15 minutes, is read again by Berthold 941
Luminescence fluorescent value.
Six, the secretase external activity experiment based on fluorogenic substrate
Cell is cracked with lysis buffer (5mMTris-HCl (pH 7.4), 5mM EDTA and 5mMEGTA), with 29G pancreas islet
Plain needle is aspirated repeatedly with smudge cells.800g is centrifuged 10 minutes in 4 DEG C, to remove big cell fragment and nucleus, takes supernatant.
Supernatant total protein concentration is measured with BCA method, takes appropriate total protein to be centrifuged 1 hour through 25,000g in 4 DEG C, abandons supernatant.Film precipitating is used
After reaction buffer is resuspended, corresponding fluorogenic substrate is added, reaction is (for alpha-secretase enzyme, 10mMTris- in 37 DEG C of metal baths
HCl, pH 7.5 reacts 1 hour；For BACE, 50mM sodium acetate, pH 4.5, react 30 minutes；For γ-points
Enzyme is secreted, 50mMTris-HCl, pH 6.8,2mM EDTA, 0.25%CHAPSO react 2 hours).Reaction product is used
M5spectrum measures fluorescent value, sets corresponding excitation wavelength λ ex and wavelength of transmitted light λ em.For alpha-secretase enzyme, λ ex=
325nm, λ em=393nm；For BACE, λ ex=430nm, λ em=520nm；For gamma-secretase, λ ex=355nm, λ em
=440nm.
Seven, data statistic analysis
All experiments are at least repeated 3 times.Experimental data is expressed as mean+/-standard error, uses
The analysis of GraphPadPrism6.01 software.Comparison for two groups of experimental datas, using Unpaired Student ' s t-
Test is analyzed；Multiple groups experimental data analyzes data using One-way ANOVA method Bonfferoni ' s multiple groups method of inspection；
p<Think there is significant difference between group when 0.05.
Unless otherwise stated, disclosed in this invention experimental method, detection method, preparation method be all made of this technology neck
Molecular biology, biochemistry, chromatin Structure and the analysis of domain routine, analytical chemistry, cell culture, recombinant DNA technology and
The routine techniques of related fields.These technologies have perfect explanation in the prior art, and for details, reference can be made to Sambrook etc.
MOLECULAR CLONING：A LABORATORY MANUAL, Second edition, Cold Spring Harbor
Laboratory Press, 1989and Third edition, 2001；Ausubel etc., CURRENT PROTOCOLS IN
MOLECULAR BIOLOGY, John Wiley&Sons, New York, 1987and periodic updates；the
Series METHODS IN ENZYMOLOGY, Academic Press, San Diego；Wolffe, CHROMATIN
STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998；METHODS IN
ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic
Press, San Diego, 1999；With METHODS IN MOLECULAR BIOLOGY, Vol.119, Chromatin
Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999 etc..
Embodiment 1QPCR detects Serotonin receptor background expression level in target cell system
SK-N-SH is one plant of neuroblastoma cell, there is composing type low-level A β to generate, in order to be confirmed whether to be suitble to
Correlative study is carried out in this cell line, we express water to intracellular Serotonin receptor background by the method for QPCR first
It is flat to be detected.As shown in Figure 1, as a result, it has been found that serotonin receptor subtype 6 has higher level in SK-N-SH cell line
Expression.
2 serotonin receptor subtype of embodiment, 6 antagonist can reduce A β in dose dependent and generate
Experiment is generated using A β, it has been found that as shown in Fig. 2, the antagonist of targeting serotonin receptor subtype 6
SB258585hydrochloride reduces A β in dose dependent and generates.
Embodiment 3SB258585hydrochloride reduces the effect that A β is generated and depends on serotonin receptor subtype 6
In order to examine whether SB258585hydrochloride reduce A β generate effect whether depend on serotonin by
Body hypotype 6, we strike low experiment by the expression of serotonin receptor subtype 6 that the method for slow virus has carried out shRNA mediation.And
The Scrambled with random nucleotides is expressed as negative control to have detected in the method for fluorescence real-time quantitative PCR
Poor efficiency is struck in the expression of serotonin receptor subtype 6 that shRNA is mediated.As shown in figure 3, the experimental result of fluorescence real-time quantitative PCR
Its mRNA level in-site can be caused to reduce 60% or so after showing virus transfection targeting 6 type shRNA of serotonin receptor subtype.With
Control group is compared, and after the shRNA of transfection targeting Serotonin receptor HTR6 sequence, in cellular control unit, antagonist stimulation is remained to
Enough reduce A β generate, and Serotonin receptor HTR6 by struck it is low after then significantly suppress antagonist reduce A β generate effect.
Embodiment 4SB258585hydrochloride, which is indirectly depended on, reduces BACE1 secretase shear active
The activity of alpha-secretase enzyme, BACE1 or gamma-secretase is related with intracellular A β generation.In order to detect
Whether the effect that SB258585hydrochloride reduces A β is by directly acting on secretase activity, we pass through glimmering
Compound and the cell membrane of extraction are carried out total incubation in vitro first by the method for light substrate, as shown in figure 4, there is no shadows for discovery
The activity to 3 secretases is rung, the effect for illustrating that SB258585hydrochloride reduces A β is not directly by influence point
Enzyme mediation is secreted, we have attempted to mention within dosing 24 hours film detection secretase activity again later, it is found that the enzyme activity of BACE1 has significantly
Downward, illustrate it is this effect be by influencing the enzyme activity of BACE1 indirectly caused by.
Embodiment 5SB258585hydrochloride reduces the warp that A beat portion depends on serotonin receptor subtype 6 to mediate
The GPCR signal path of allusion quotation
There is the constitutive activity in the case of background based on existing report confirmation serotonin receptor subtype 6, then
Whether SB258585hydrochloride can reduce the cAMP expression of its background level as its inverse agonist and mediate A β
Reduction, by the way that the cell after 72 hours of virus infection pGlo-20F and HTR6 is laid on white 96 orifice plates, after 24 hours more
Changing training liquid is the training liquid containing 2%GloSensor Reagent, and 37 DEG C are incubated for 1.5 hours, and the antagonism of concentration gradient is then added
Agent, detects cAMP again after being incubated for 15 minutes, discovery SB258585hydrochloride can actually cause cell receptor to cause
Constitutive activity mediate cAMP level reduce.Then we also a degree of can inhibit antagonist to be situated between by striking low G α
The effect for reducing A β and generating led, it is sub- dependent on Serotonin receptor to illustrate that SB258585hydrochloride reduces A beat portion
The classical GPCR signal path that type 6 mediates.
Embodiment 6SB258585hydrochloride reduces A beat portion dependent on serotonin receptor subtype 6 and CDK5's
Interaction
Existing research shows that SB258585hydrochloride can interfere serotonin receptor subtype 6 and CDK5's
Interaction, then we are examined with WB with low CDK5 is struck and are struck poor efficiency, compared with the control group, target shRNA points of source of people
Low expression about 70% can not be struck significantly, and the method discovery of subsequent CDK5 inhibitor a degree of can also inhibit ligand-mediated
Reduce A β generate effect, illustrate SB258585hydrochloride reduction partly depend on 6 receptor of serotonin with
The interaction of CDK5.
Embodiment 7SB258585hydrochloride reduces the β-that A beat portion depends on serotonin receptor subtype 6 to mediate
Arrestin2 signal path
Next we detect whether that the β-arrestin 2 of shRNA mediation strikes low energy and enough influences SB258585
Hydrochloride reduces the effect that A β is generated.We infect dye targeting source of people in SK-N-SH cell first
After the shRNA of ARRB2, is examined with WB and strike poor efficiency.Compared with the control group, the shRNA for targeting source of people is able to significantly strike
Low expression about 60%.On this basis, we give antagonist processing, have detected cell A β generation.The result shows that striking low ARRB2
Being able to suppress SB258585hydrochloride reduces the effect that A β is generated.
Other 6 activator of serotonin receptor subtype of embodiment 8 and antagonist can also reduce A β generation
Experiment is generated using A β, we have detected other several 6 antagonists of serotonin receptor subtype and 1 pentahydroxy- color again
The effect that 6 activator of amine receptor hypotype (ST1936oxalate) generates A β, as a result, it has been found that either activator or antagonist
A β can be reduced in dose dependent to generate.
It discusses：
The present invention is experiments have shown that the activator and antagonist of serotonin receptor subtype 6 can be fastened in the nerve cell of people
A β is reduced to generate.In using several activator and antagonist, activator ST1936 and antagonist
SB25858hydrochloride does not enter clinical research, and SB271046hydrochloride is due to the problem of crossing blood-brain barrier
Clinical research was terminated in 2003, idalopirdine tests expected 3 phase of clinic for terminating at last year due to being not up to, and another
One drug Intepirdine is then to create within nearly 2 years the mythical Axovant company of financing repeatly to buy from GSK, and how also prospect
It cannot judge easily.The 5-HT6 antagonist development time, indication was nearly all the neurologicals such as AD and Parkinson close to 20 years
Property disease, and the clinical effectiveness that the antagonist why having shows is preferable, and some was had to terminate in some clinical period, this its
In reason be still complicated, and we for SB258585hydrochloride targeting 6 receptor of serotonin reduce
The mechanism for the muliti-pathway that A β is generated also gives this problem some enlightenments, i.e., is equally all whether antagonist can be due to opening
Effect is different caused by dynamic downstream mechanism is different, therefore, targets the activator and antagonist drop of serotonin receptor subtype 6
Low A β is generated and the announcement of related mechanism can provide clinical trial for the treatment of Alzheimer's disease and further medicament research and development
Directive significance.
The above, only presently preferred embodiments of the present invention, not to the present invention in any form with substantial limitation,
It should be pointed out that under the premise of not departing from the method for the present invention, can also be made for those skilled in the art
Several improvement and supplement, these are improved and supplement also should be regarded as protection scope of the present invention.All those skilled in the art,
Without departing from the spirit and scope of the present invention, when made using disclosed above technology contents it is a little more
Dynamic, modification and the equivalent variations developed, are equivalent embodiment of the invention；Meanwhile all substantial technologicals pair according to the present invention
The variation, modification and evolution of any equivalent variations made by above-described embodiment, still fall within the range of technical solution of the present invention
It is interior.
Claims (11)
1. the antagonist of serotonin receptor subtype 6 is preparing the purposes in amyloid A beta inhibitor.
2. purposes according to claim 1, which is characterized in that the antagonist of the serotonin receptor subtype 6 can press down
Amyloid A β processed generates or reduces amyloid A β level.
3. the purposes according to weighing and require 1, which is characterized in that the antagonist of the serotonin receptor subtype 6 is selected from
SB258585hydrochloride、SB271046hydrochloride、Intepirdine RVT-101、Idalopirdine。
4. purposes according to claim 3, which is characterized in that further include any one or multinomial of following characteristics：
(1) SB258585hydrochloride inhibits amyloid A β to generate by acting on serotonin receptor subtype 6
Or reduce amyloid A β level；
(2) SB258585hydrochloride inhibits amyloid A β to generate or drop by reducing BACE1 secretase activity
Low amyloid A β is horizontal；
(3) SB258585hydrochloride is logical by the classical GPCR signal for acting on the mediation of serotonin receptor subtype 6
To inhibit, amyloid A β is generated or reduction amyloid A β is horizontal on road；
(4) SB258585hydrochloride inhibits to form sediment by interfering the interaction of serotonin receptor subtype 6 and CDK5
Powder sample albumin A β generates or reduces amyloid A β level；
(5) β-arrestin2 signal that SB258585hydrochloride is mediated by acting on serotonin receptor subtype 6
To inhibit, amyloid A β is generated access or reduction amyloid A β is horizontal.
5.SB258585hydrochloride preparing the purposes in BACE1 Secretase inhibitors.
6. purposes according to claim 4, which is characterized in that the SB258585hydrochloride can reduce
BACE1 secretase shear active.
Purposes of the 7.SB258585hydrochloride in the constitutive activity inhibitor for preparing serotonin receptor subtype 6.
8. purposes according to claim 6, which is characterized in that the SB258585hydrochloride can reduce five
The cAMP that the constitutive activity of HT receptor subtypes 6 mediates is horizontal.
9. the activator of serotonin receptor subtype 6 is preparing the purposes in amyloid A beta inhibitor.
10. purposes according to claim 8, which is characterized in that the activator is selected from ST1936oxalate.
11. a kind of method for inhibiting amyloid A β, including step：By the antagonist of serotonin receptor subtype 6 or activation
Agent is applied to object.
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| CN111214661A (en) * | 2020-02-29 | 2020-06-02 | 同济大学 | Application of compound for inhibiting Htr3a and intracellular signal pathway thereof in preparation of drugs for treating and/or preventing AD |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5962463A (en) * | 1992-10-09 | 1999-10-05 | Massachusetts Institute Of Technology | Methods of stimulating non-amyloidogenic processing of the amyloid precursor protein |
| US20030069233A1 (en) * | 1996-12-19 | 2003-04-10 | Smithkline Beecham P.L.C. | Sulphonamide derivatives, process for their preparation, and their use as medicaments |
| CN1535146A (en) * | 2001-06-21 | 2004-10-06 | ϣ��������ҩ��ҵ��˾ | 5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors |
| US20060084676A1 (en) * | 2004-10-20 | 2006-04-20 | Churlmin Seong | 3-aryl--3-methyl-quinoline-2, 4-diones, preparation method thereof, and pharmaceutical composition containing the same |
| CN101031338A (en) * | 2004-09-30 | 2007-09-05 | 弗·哈夫曼-拉罗切有限公司 | Compositions and methods for treating cognitive disorders |
| KR20080004994A (en) * | 2006-07-07 | 2008-01-10 | 한국과학기술연구원 | Cell-based high-throughput screening method of 5-ht6 receptors using fluorescence calcium imaging |
| RU2491281C1 (en) * | 2012-07-05 | 2013-08-27 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук (ИМГ РАН) | Uniformly tritiated 4-iodo-n-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzensuphonamide |
-
2017
- 2017-05-26 CN CN201710384817.7A patent/CN108926565A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5962463A (en) * | 1992-10-09 | 1999-10-05 | Massachusetts Institute Of Technology | Methods of stimulating non-amyloidogenic processing of the amyloid precursor protein |
| US20030069233A1 (en) * | 1996-12-19 | 2003-04-10 | Smithkline Beecham P.L.C. | Sulphonamide derivatives, process for their preparation, and their use as medicaments |
| CN1535146A (en) * | 2001-06-21 | 2004-10-06 | ϣ��������ҩ��ҵ��˾ | 5-halo-tryptamine derivatives used as ligands of 5-HT 6 and/or 5-HT7 serotonin receptors |
| CN101031338A (en) * | 2004-09-30 | 2007-09-05 | 弗·哈夫曼-拉罗切有限公司 | Compositions and methods for treating cognitive disorders |
| US20060084676A1 (en) * | 2004-10-20 | 2006-04-20 | Churlmin Seong | 3-aryl--3-methyl-quinoline-2, 4-diones, preparation method thereof, and pharmaceutical composition containing the same |
| KR20080004994A (en) * | 2006-07-07 | 2008-01-10 | 한국과학기술연구원 | Cell-based high-throughput screening method of 5-ht6 receptors using fluorescence calcium imaging |
| RU2491281C1 (en) * | 2012-07-05 | 2013-08-27 | Федеральное государственное бюджетное учреждение науки Институт молекулярной генетики Российской академии наук (ИМГ РАН) | Uniformly tritiated 4-iodo-n-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzensuphonamide |
Non-Patent Citations (6)
| Title |
|---|
| ANDREAS GRAVIUS等: "Effects of 5-HT6 antagonists, Ro-4368554 and SB-258585, in tests used for the detection of cognitive enhancement and antipsychotic-like activity", 《BEHAVIOURAL PHARMACOLOGY》 * |
| MARIA J. RAMIREZ等: "Serotonergic therapies for cognitive symptoms in Alzheimer"s disease: rationale and current statu", 《DRUGS》 * |
| MARÍA JAVIER RAMÍREZ: "5-HT6 receptors and Alzheimer"s disease", 《RAMÍREZ ALZHEIMER’S RESEARCH & THERAPY》 * |
| XIAOHANG LI等: "A tricyclic antidepressant, amoxapine, reduces amyloid-β generation through multiple serotonin receptor 6-mediated targets", 《SCIENTIFIC REPORTS》 * |
| 刘学伍等主编: "《神经病学新理论新技术》", 31 December 2009, 人民军医出版社 * |
| 刘新民主编: "《内科学 第一卷》", 31 July 2008, 军事医学科学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111214661A (en) * | 2020-02-29 | 2020-06-02 | 同济大学 | Application of compound for inhibiting Htr3a and intracellular signal pathway thereof in preparation of drugs for treating and/or preventing AD |
| CN111214661B (en) * | 2020-02-29 | 2021-09-03 | 同济大学 | Application of compound for inhibiting Htr3a and intracellular signal pathway thereof in preparation of drugs for treating and/or preventing AD |
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