CN106188246A - N methyl D aspartate receptor agonist polypeptide and application - Google Patents
N methyl D aspartate receptor agonist polypeptide and application Download PDFInfo
- Publication number
- CN106188246A CN106188246A CN201610768165.2A CN201610768165A CN106188246A CN 106188246 A CN106188246 A CN 106188246A CN 201610768165 A CN201610768165 A CN 201610768165A CN 106188246 A CN106188246 A CN 106188246A
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- China
- Prior art keywords
- polypeptide
- methyl
- present
- group
- aspartate receptor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The present invention relates to drug world, be specifically related to that there is suppression N methyl D aspartate receptor, alleviate the polypeptide of depressive symptom.Its sequence is brand-new sequence, and it has the beneficial effects that, the many Toplink of the present invention significantly inhibit hippocampus of rats cell nmda receptor electric current, and its IC50 value is 3.81 ± 0.72 μMs.Showing at body Pharmacological Results, the many Toplink of the present invention improve the depressive symptom of acute and chronic depression model animal.Can be as the effective candidate therapeutics of clinical depression.
Description
Technical field
The present invention relates to N-methyl-D-aspartate receptor antagonist polypeptide and application thereof, be specifically related to that there is suppression N-
Methyl-D-asparagic acid acceptor, alleviates the polypeptide of depressive symptom.
Background technology
Depression is by mental sickness of concern.Although depression is just with us, but patient
Connecing subject ratio the highest, the treating depression rate of China, less than 10%, even if in developed country, is also less than half.
It is a kind of mental status that a lot of people merely serve as depression, and when this idea also tends to cause patient to miss optimal treatment
Machine.Due to pressure and the lifestyle change of modern society, in the adult more than 20 years old, the sickness rate of depression is just with every year
The speed increment of 11.3%.And in the middle of teenager, depression also presents the trend risen year by year.Depression will be only second to lack
Courageous and upright heart disease, becomes the second largest reason that the mankind are disabled and dead.
Current research proposes, the glutamate receptor exception hypothesis of depression, and thinks Drug therapy novel targets.Ion-type paddy
Propylhomoserin receptor N-methyl-D-aspartate (NMDA) receptor and alpha-amido-3-hydroxy-5-methyl base-4-isoxazole propanoic acid (AMPA)
Receptor is, with depression, two kinds of mostly concerned glutamate receptors occur, and this receptoroid can allow the sun such as Na+, Ca2+ when activating
Ion passes through.Additionally, the film outboard end of nmda receptor exists the binding site of glycine (glycine), in passage, then there is Mg2+
Binding site, these are all the critical sites of nmda receptor function regulation.In physiological conditions, the ampa receptor of postsynaptic membrane and
The activation of nmda receptor (predominantly NR2A receptor subtype) is synaptic plasticity and the important electro physiology of ability of learning and memory enhancing
Mechanism；And in the pathological processes such as glutamate excitotoxicity damage, Extrasynaptic NMDA receptor (predominantly NR2B receptor subtype)
Activation then can cause Ca2+ overload, oxidativestress damage and the depressive symptom such as apoptosis or degeneration.Therefore, NMDA is subject to
Body inhibitor becomes the novel targets for the treatment of depression and the focus of research.
But, the nmda receptor inhibitor of present stage has ketamine, phencyclidine, is not used for treating depression.
Summary of the invention
Goal of the invention
The present invention provides brand-new sequence, this sequence N-methyl-D-aspartate receptor antagonist polypeptide, has depression
There is good curative effect.
Technical scheme
N-methyl-D-aspartate receptor antagonist polypeptide, it is characterised in that its sequence is SEQ ID NO:1.
The application in medicament for treatment of depression of the N-methyl-D-aspartate receptor antagonist polypeptide.
Beneficial effect
Utilizing solid-phase synthesis chemosynthesis N-methyl-D-aspartate receptor antagonist polypeptide, this polypeptide has completely newly
Sequence, this polypeptide can be used for treat depression.Molecular results shows, the many Toplink of N-methyl-D-aspartate receptor antagonist
Significantly inhibiting hippocampus of rats cell nmda receptor electric current, its IC50 value is 3.81 ± 0.72 μMs.Show at body Pharmacological Results
Showing, the polypeptide of the present invention can reduce in Tail suspension test stress outstanding tail time of desperate model mice；Also mice can be reduced
Stress forced swimming time of desperate model mice in forced swim test；Meanwhile, polypeptide of the present invention can reduce chronic can not
Prediction the looking for food incubation period of Stress model rat, improves its picked-up to sucrose solution in sucrose solution is tested, compared with model group, has
Significant difference.Looking for food, predominantly detect incubation period is rat anxiety-like behavior, and rat sucrose solution preference table understands the interest of rat
Disappearance tendency.As can be seen here, the many Toplink of the present invention improve the depressive symptom of acute and chronic depression model animal.Can be as facing
The bed effective candidate therapeutics of depression.
Detailed description of the invention
Polypeptide is by Shanghai raw work gill synthesis.
Embodiment 1
N-methyl-D-aspartate receptor antagonist polypeptide is to hippocampus of rats N-methyl-D-aspartate receptor
Electric current inhibitory action.
Use full cell patch technical notes cultured hippocampal neuronal NMDA receptor electric current.SD in raw 24h is big
Extract in Mus brain, hippocampal neuron, 37 DEG C, cultivate in the incubator of 5%CO2 and carry out patch clamp experiments in 8-13 days.
Whole-cell recording instrument is CEZ-2400 patch clamp amplifier (Japan Nihon Kohden), glass
Microelectrode is filled interior liquid composition (mmol/L): KCl 140, CaCl2 1, MgCl2 2, HEPES 10, EGTA 11, ATP 4, uses
PH value is adjusted to 7.2 by 1M KOH, with sucrose, osmotic pressure is adjusted to 310mOsm/L, electrode resistance 3-5M Ω.Perfusion is with outer liquid composition
(mmol/L): NaCl 150, KCl 5, CaCl2 2.5, HEPES 10, D-Glucose 10, tetrodotoxin 0.0002, use 1M
PH value is adjusted to 7.4 by NaOH, with sucrose, osmotic pressure is adjusted to 340mOsm/L.By microelectrode on cell membrane, at electrode and cell
After forming high resistant (1-5G Ω) sealing-in between film, being suctioned through by film further, regulation electric capacity and series resistance compensation, transmembrane potential is clamped down on
In-50mV, membrane current application low-pass filtering (1Hz ,-3dB), record experimental result.
The whole solution of the different gradient concentration of polypeptide extracellular fluid of the present invention preparation, pH is adjusted to 7.4.Administering mode is by micro-
Manipulator move homemade quick liquid changing device comb be administered, often the diameter (O.D/I.D) of pipe is 500/200 μm, the mouth of pipe away from
From record cell about 100 μm.Experiment is carried out in the range of room temperature 22-25 DEG C.The different gradient concentration polypeptide of record is to rat hippocampus
Neuronal NMDA receptor current data.
Showing in hippocampus of rats nmda receptor results of weak current, polypeptide of the present invention can suppress stream in cation, its
IC50 value is 3.81 ± 0.72 μMs.
Embodiment 2
N-methyl-D-aspartate receptor antagonist polypeptide stress the impact of desperate model on mouse forced swimming test.
Using ICR mice as animal subject, take 50 mices, male and female half and half, body weight is 18-22g, is randomly divided into 5 groups:
High dose group, middle dosage group, low dose group, positive controls, blank group, often group l0 is only.The group subcutaneous injection present invention is many in treatment
Peptide, dosage is respectively 20,10,5mg/Kg, matched group fluoxetine, dosage is 10mg/Kg, and blank group gives normal saline, continuously
It is administered 7 days.1h after being administered for 7th day, mice carries out forced swim test, and mice is forced swimming 6min in 20-25 DEG C of water, record
Dead time in rear 4min, the dead time, it is mice and stops struggling in water, only by the time floating for head above water, with
This evaluates polypeptide of the present invention stress the impact of desperate model on mouse forced swimming test.
Table 1 polypeptide of the present invention stress the impact of desperate model on mouse forced swimming test
* p < 0.05, * * p < 0.01 is compared with blank group
Polypeptide of the present invention to mouse forced swimming test stress desperate model result as shown in Table 1: polypeptide of the present invention can reduce
Forced swimming time in mice, is dose dependent when dosage is at 5-20mg/Kg, compared with blank group, has significant difference.
Embodiment 3
N-methyl-D-aspartate receptor antagonist polypeptide stress the impact of desperate model on mouse tail suspension.
Using ICR mice as animal subject, take 50 mices, male and female half and half, body weight is 18-22g, is randomly divided into 5 groups:
High dose group, middle dosage group, low dose group, positive controls, blank group, often group l0 is only.The group subcutaneous injection present invention is many in treatment
Peptide, dosage is respectively 20,10,5mg/Kg, matched group fluoxetine, dosage is 10mg/Kg, and blank group gives normal saline, continuously
It is administered 7 days.1h after being administered for 7th day, mice carries out tail-suspention test, and mice adhesive tape is fixed on its afterbody at end about 1cm,
Making mice keep suspension status 6min, the dead time of 4min after record, evaluating polypeptide of the present invention with this stress to mouse tail suspension
The impact of desperate model.
Table 2 polypeptide of the present invention stress the impact of desperate model on mouse tail suspension
* p < 0.05, * * p < 0.01 is compared with blank group
Polypeptide of the present invention to mouse tail suspension stress desperate model result as shown in Table 2: polypeptide of the present invention can reduce mice
The outstanding tail time, is dose dependent when dosage is at 5-20mg/Kg, compared with blank group, has significant difference.
Embodiment 4
The impact of N-methyl-D-aspartate receptor antagonist polypeptide Stress model unpredictable on rat chronic.
Using SD rat as animal subject, take 60 rats, male and female half and half, body weight is 180-220g, is randomly divided into 6
Group, high dose group, middle dosage group, low dose group, positive controls, model group, blank group, often group l0 is only.Set up rat chronic
Unpredictable Stress model: stress content be: constraint 4h；Wet bedding and padding are overnight；Rock 1h (160r/min)；Fasting 12h；Frozen water is swum
Swim 4 DEG C, 10min；Rearging cage tilts 45 ° overnight；Folder tail 1min；Crowded overnight (8/cage).Use daytime two kinds stress, night
Use one stress, continuously stress 4 weeks.It is administered after last stimulation.Dosage regimen: the group subcutaneous injection present invention is many in treatment
Peptide, dosage is respectively 20,10,5mg/Kg, matched group fluoxetine, dosage is 10mg/Kg, and blank group gives normal saline, continuously
It is administered 7 days.7th day be administered after 1h, rat carry out novelty look for food incubation period experiment and sucrose solution preference test, evaluate the present invention with this
The impact of polypeptide Stress model unpredictable on rat chronic.Novelty is looked for food and is tested i.e. incubation period: laboratory animal is carrying out 24h taboo
After food, animal is placed in the spacious field that length × width × height is 76.5cm × 76.5cm × 40cm, is placed with certain in the middle of spacious field
The food of amount, animal is put into from one jiao of spacious field, observes animal and successfully looks for food the spent time in 5min.Simultaneously after test
Measure the animal food gross weight at 5min internal consumption, in this, as the most consistent with reference to carrying out judgment experiment animal hunger intensity.
Sucrose solution preference is tested i.e.: adapts to 48h with the sucrose solution of 1% by animal before sucrose solution detects, is placed in by animal and is placed with two after prohibiting water 4h
In the rearging cage of individual identical water bottle.These two water bottles one only fill the sucrose solution of 1%, and another is equipped with tap water.In record 1h often
Rat drinks the volume of sucrose solution and tap water respectively.The sucrose solution volume of sucrose solution preference=drink/(the sucrose solution volume drunk+from
Water cumulative volume) × 100%.
The impact of table 3 polypeptide of the present invention Stress model unpredictable on rat chronic
* p < 0.05, * * p < 0.01 is compared with model group
Polypeptide of the present invention Stress model unpredictable to rat chronic result is as shown in Table 3: polypeptide of the present invention can reduce
Looking for food incubation period of model group rats, improves the picked-up to sucrose solution in the experiment of chronic unpredictable Stress model rat sucrose solution, with
Model group is compared, and has significant difference.Looking for food, predominantly detect incubation period is rat anxiety-like behavior, rat sucrose solution preference table
Understand the anhedonia tendency of rat.As can be seen here, the many Toplink of the present invention improve pressing down of chronic unpredictable Stress model rat
Strongly fragrant symptom.
SEQUENCE LISTING
<110>Suzhou Pu Luoda bio tech ltd
<120>N-methyl-D-aspartate receptor antagonist polypeptide and application thereof
<130>
<160> 1
<170> Patent In version 3.3
<210> 1
<211> 45
<212> PRT
<213>artificial sequence
<400> 1
Gln Tyr Ile Glu Phe Ser Lys Pro Phe Lys Tyr Gln Gly Leu Thr Ile
1 5 10 15
Leu Val Lys Lys Gly Thr Arg Ile Thr Gly Ile Asn Asp Pro Arg Leu
20 25 30
Arg Asn Pro Ser Asp Lys Phe Ile Tyr Ala Thr Val Lys
35 40 45
Claims (2)
1.N-methyl-D-aspartate receptor agonist polypeptide, it is characterised in that its sequence is SEQ ID NO:1.
The application in medicament for treatment of depression of the 2.N-methyl-D-aspartate receptor agonist polypeptide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610768165.2A CN106188246A (en) | 2016-08-30 | 2016-08-30 | N methyl D aspartate receptor agonist polypeptide and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610768165.2A CN106188246A (en) | 2016-08-30 | 2016-08-30 | N methyl D aspartate receptor agonist polypeptide and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106188246A true CN106188246A (en) | 2016-12-07 |
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ID=58089047
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610768165.2A Pending CN106188246A (en) | 2016-08-30 | 2016-08-30 | N methyl D aspartate receptor agonist polypeptide and application |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918020A (en) * | 2007-11-14 | 2010-12-15 | 艾罗文斯公司 | The IL-4 mutein receptor antagonists of modifying |
| CN103102393A (en) * | 2013-01-30 | 2013-05-15 | 北京大学 | Polypeptide and application of polypeptide in preparation of drug used for treating depression |
-
2016
- 2016-08-30 CN CN201610768165.2A patent/CN106188246A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101918020A (en) * | 2007-11-14 | 2010-12-15 | 艾罗文斯公司 | The IL-4 mutein receptor antagonists of modifying |
| CN103102393A (en) * | 2013-01-30 | 2013-05-15 | 北京大学 | Polypeptide and application of polypeptide in preparation of drug used for treating depression |
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Application publication date: 20161207 |
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