CN107823199A - Application of the nepetalactone derivative in nerve degenerative diseases are treated - Google Patents
Application of the nepetalactone derivative in nerve degenerative diseases are treated Download PDFInfo
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- CN107823199A CN107823199A CN201711114558.2A CN201711114558A CN107823199A CN 107823199 A CN107823199 A CN 107823199A CN 201711114558 A CN201711114558 A CN 201711114558A CN 107823199 A CN107823199 A CN 107823199A
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- Prior art keywords
- nepetalactone
- degenerative diseases
- nerve degenerative
- derivative
- medicine
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
Abstract
The invention provides the application of nepetalactone and its derivative in nerve degenerative diseases are treated.Experiment finds that nepetalactone and its derivative have the bioactivity of protection neuronal cell, therefore can be prepared into medicine by adding auxiliary material, available for the prevention and treatment of nerve degenerative diseases, is especially suitable for treatment Parkinson's.
Description
Technical field
The invention belongs to the bioactivity technical field of compound, exist in particular to nepetalactone and its derivative
Treat the application in nerve degenerative diseases.
Background technology
Nerve degenerative diseases (Neurodegenerative disease) are the cellular neural member funerals of a brain and spinal cord
The morbid state of mistake.Brain and spinal cord are made up of neuron, and neuron has different functions, and letter is felt in such as control motion, processing
Breath, and make decisions.The cell of brain and spinal cord is usually what will not be regenerated, so excessive infringement is probably destructive,
It is irreversible.Nerve degenerative diseases are caused by the forfeiture of neuron or its myelin, are deteriorated over time, with
Cause dysfunction.Nervus retrogression disease is divided into two groups by phenotype：One kind is to influence motion, such as cerebellar ataxia；It is another
Class is the dementia for influenceing memory and correlation.Principal disease include Alzheimer disease (Alzheimer ' s disease,
AD), Parkinson's (Parkinson ' s disease, PD), Huntington disease (Huntington disease, HD), amyotrophic side
Rope sclerosis (amyotrophic lateral sclerosis, ALS) etc..
Parkinson's are most common kinetic system degenerative diseases, and main clinical manifestation is：Static tremor, action
Slow, astasia and attitudinal reflex obstacle.The major lesions position of Parkinsonian's brain is black substance and corpus straitum, its
The death of dopaminergic neuron and quantity, which are reduced, in middle substantia nigra compacta causes to project Dopamine In Striatum reduction
Immediate cause.At present, PD mechanism of causing a disease also less clearly, but with diabetes complicated encephalopathic caused by oxidative damage, hippocampus god
There is obvious difference through diseases such as first Apoptosis.PD is as the second largest nervus retrogression disease for being only second to Alzheimer's disease
Disease, Parkinson's sharply increase with its incidence of disease of the increase at age and illness rate, and illness rate reaches in the elderly more than 60 years old
1%, crowd reaches 5%-6% within more than 85 years old, and Parkinsonian's quantity in China is more than 2,000,000 at present.The PD cause of disease and aging,
Environment and inherent cause are relevant, and PD pathogenesis is still indefinite at present.But research show, oxidativestress damage, immune inflammation,
The pathomechanisms such as er stress, apoptosis interact, and may cause PD occurrence and development.China has progressed at present
Aging society, with the increase of the aged, the quantity of PD patient will also increase sharply.PD is not only making to patient in the action
Into inconvenience, some patients can spiritedness and disturbance of intelligence, thousands of family is also enjoyed torment in spirit, therefore, from
Multipath treatment PD turns into current study hotspot.
At present, the clinical treatment for Parkinson's mainly has chemotherapy and surgical operation therapy, and still locates
Cell therapy and gene therapy in the experimental stage." gold of the chemotherapy using Benserazide preparation as treatment PD
Standard ", but this is the short term efficacy further to injure the functional status of dopaminergic neuron as cost, in control symptom side
Face is better than Chinese medicine, but prolonged application, and toxic side effect is big, and not only curative effect gradually weakens with time lengthening, terminated, and can accelerate
The death rate of the existing dopaminergic neuron of patient, is tantamount to drink poison to quench thirst from long-term effect.Traditional Chinese medicine monomer is with its poison
The lasting and integrally-regulated advantage such as good of Small side effects, curative effect, it has also become the research for preventing and treating PD new drugs in recent years is oriented to.
Nepetalactone is by extracting a kind of isolated Loliolide in Chinese medicine schizonepeta, can be used for preparing anti-flu
Medicine, anti-inflammation drugs, antibacterials, analgestic etc..By retrieving domestic and foreign literature, at present still without nepetalactone or its derivative
Document report in terms of thing treatment nerve degenerative diseases.
The content of the invention
In view of the deficiencies in the prior art, it is an object of the invention to provide nepetalactone and its derivative to move back in treatment nerve
Application in row disease.
In order to realize the purpose of the present invention, inventor by substantial amounts of cell assay in vitro study and persistent exploration after send out
Existing, nepetalactone has significant protective effect to neuronal cell, so as to confirm that the compound has treatment neurological
The bioactivity of property disease.However, bioactivity of the nepetalactone in terms of neuronal cell is protected is unsatisfactory, therefore invent
People carries out structural modification according to structure-activity relationship to the compound for many years, is finally obtained a kind of effect highly significantization schizonepeta
Lactone derivatives.
Therefore, technical scheme overview provided by the invention is：Nepetalactone or derivatives thereof is preparing treatment neurological
Applied in the medicine of property disease.Wherein, the molecular formula of nepetalactone is C10H14O3, its structural formula is as follows：
It is further preferred that nepetalactone or derivatives thereof is preparing the medicine for the treatment of nerve degenerative diseases as described above
Middle application, nepetalactone derivative therein are nepetalactone fluorobenzoate, and its structural formula is as follows：
Found in the other experiment of the present invention, nepetalactone and its derivative are particularly suitable for preventing or treat pa gold
Gloomy disease, therefore nepetalactone further preferably as described above or derivatives thereof is in the medicine for preparing treatment nerve degenerative diseases
Using wherein nerve degenerative diseases are Parkinson's.
Still further preferably, nepetalactone as described above or derivatives thereof is preparing the medicine for the treatment of nerve degenerative diseases
Applied in thing, nepetalactone therein be its raceme, stereoisomer, solvate or enter body after be metabolized as in schizonepeta
The precursor compound of ester；Nepetalactone fluorobenzoate therein is its raceme, stereoisomer, solvate or into machine
The precursor compound of nepetalactone fluorobenzoate is metabolized as after body.
It should be noted that nepetalactone or derivatives thereof is preparing the medicine for the treatment of nerve degenerative diseases as described above
Middle application, medicine therein are preferably solid orally ingestible, including ordinary tablet, dispersible tablet, enteric coatel tablets, oral disintegrating tablet, sustained release tablets, glue
Capsule, granule.These oral formulations can add available auxiliary material in pharmacy, such as on the basis of above-mentioned active component
Include but are not limited to filler (diluent), disintegrant, lubricant (glidant), adhesive, solubilizer, antioxidant, emulsification
Agent, sustained-release matrix material, coating powder etc., it is prepared by the conventional formulation technique of this area.Wherein, filler includes breast
Sugar, Icing Sugar, dextrin, starch and its derivative, cellulose and its derivates, inorganic calcium salt (such as calcium sulfate, calcium phosphate, phosphoric acid hydrogen
Calcium, precipitated calcium carbonate etc.), sorbierite or glycine etc.；Disintegrant includes sodium carboxymethyl starch, PVPP, crosslinking carboxylic first
Base sodium cellulosate and low-substituted hydroxypropyl cellulose；Adhesive includes syrup, cellulose and its derivates (such as hydroxypropyl methylcellulose
Element etc.), starch slurry or polyvinylpyrrolidone etc.；Lubricant includes superfine silica gel powder, magnesium stearate, talcum powder, aluminium hydroxide, boron
Acid, hydrogenated vegetable oil, polyethylene glycol etc.；Antioxidant packages are containing sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, dibutyl benzoic acid
Deng；Emulsifying agent includes Tween-80, does not have that sour sorb is smooth, pluronic gram F-68, lecithin, Fabaceous Lecithin etc..
Compared with prior art, present invention firstly discovers that nepetalactone and its derivative have the life of protection neuronal cell
Thing activity, the prevention and treatment that medicine is used for nerve degenerative diseases can be prepared into, be especially suitable for treatment Parkinson's.In addition,
Because nepetalactone and its derivative are as active component, it derives from natural plants or its trim, therefore toxic side effect is small,
It is easier to be accepted by patients.
Embodiment
It is the preparation embodiment and test examples of the present invention below, the present invention will be further explained, but the present invention
Protection domain be not limited to following examples.
Embodiment one：The preparation of nepetalactone fluorobenzoate
Nepetalactone sterling 36.4mg, m-fluorobenzoic acid 53.0mg, and DMAP 24.5mg are weighed, by it
It is placed in round-bottomed flask, add 6mL dichloromethane is completely dissolved it as reaction dissolvent, stirring, adds 1- (3- dimethylaminos
Propyl group) -3- ethyl-carbodiimide hydrochloride 72.5mg, in 25 DEG C of fully reactions, TLC examines reaction end.After reaction terminates, drop
Add methanol to clarify solution, add the silica gel about 600mg of column chromatography, stir the lower solvent that is evaporated under reduced pressure to dry.Weigh 6g silica gel
Post is filled, with petroleum ether:Ethyl acetate=6:1 is eluted as eluant, eluent, and TLC tracking can find target compound nepetalactone
Fluorobenzoate, eluent is now collected, merge eluent, eluent is recovered under reduced pressure, it is white that nepetalactone fluorobenzoate can be obtained
Color crystalline powder, purity 97.61%, yield 84.6%.
Embodiment two：The preparation of nepetalactone fluorobenzoate
Nepetalactone sterling 54.5mg, m-fluorobenzoic acid 105.3mg, and DMAP 36.9mg are weighed, will
It is placed in round-bottomed flask, and add 10mL dichloromethane is completely dissolved it as reaction dissolvent, stirring, adds N, the rings of N'- bis-
Hexyl carbodiimide 154.8mg, in 25 DEG C of fully reactions, TLC examines reaction end.After reaction terminates, methanol, which is added dropwise, makes solution
Clarification, the silica gel about 1500mg of column chromatography is added, stir the lower solvent that is evaporated under reduced pressure to dry.15g silica gel dress post is weighed, with oil
Ether:Ethyl acetate=7:1 is eluted as eluant, eluent, and TLC tracking can find target compound nepetalactone fluorobenzoate,
Eluent is now collected, merges eluent, eluent is recovered under reduced pressure, nepetalactone fluorobenzoate white crystalline powder can be obtained
End, purity 97.10%, yield 83.8%.
Embodiment three：Influence experimental study of the nepetalactone fluorobenzoate to extracorporeal neuron cell
Hippocampus neurons in mice cell HT-22 cells are taken, is digested with 1mL0.25% pancreatin and dispels into single cell suspension,
Add a small amount of hyclone FBS (100 μ L).1000rpm centrifuges 5min, removes supernatant, cell precipitation is dispersed in into 3mL cultivates completely
In base, take 1mL cell suspensions to be added in 24mL complete mediums, overturn 10 mixings back and forth, take 0.1mL to be used to count.It is dilute
Release to 8 × 104After cell/mL cell concentrations, 96 orifice plates first add 50 μ L culture mediums, culture medium is thoroughly distributed in orifice plate rims,
Then by cell seeding in 96 orifice plates.The rotating centrifugal pipe in kind, one half bore of kind firmly blow and beat cell, are allowed to uniform, simultaneously
Allow cell suspension to be paved with orifice plate bottom, observe whether cell is scattered uniform, and cross, which shakes up, to be made carefully after all finishing under the microscope
Born of the same parents are uniformly dispersed in orifice plate bottom.Place 24 hours or so, be used to test when cell fusion degree is about 30~40%.
0.02 μm of μ g of nepetalactone 10, μ g of nepetalactone fluorobenzoate 10, watermiscible vitamin E ol are scattered in respectively
It is standby in 2mL complete mediums.96 orifice plates of kind good cell are taken, are divided into Normal group, model control group, vitamin E group,
Nepetalactone group and nepetalactone fluorobenzoate group.Every group of 6 multiple holes, culture medium change liquid (Normal group and model comparison
Group changes liquid using the complete medium for being not added with medicine), per the μ L of hole 200, before changing liquid every time, culture medium is blown and beaten, makes medicine scattered equal
It is even.Changing addition glutamic acid after complete 37 DEG C of liquid is incubated 1h makes final concentration reach 3mM (Normal group is not added with glutamic acid).Put after shaking up
Put and cultivate 24h at 37 DEG C, then observe cellular morphology, mtt assay detection cell survival rate, then with 20 μ L MTT (5mg/mL)
37 DEG C of incubation 2h of lucifuge, gently suck liquid, add 200 μ L DMSO, shaking table 5min to shake up per hole.Then multi-function microplate reader is used
Calculate each light absorption value under 490nm.The hole OD values of each group 6 are taken, averages, subtracts blank DMSO OD values, it is then divided by normal right
According to the standardizing average values of group.
Nepetalactone fluorobenzoate group and nepetalactone group, vitamin can be seen that by the test statistics result of table 1
E groups are obviously improved compared to the cell survival rate of model control group, and its difference has statistical significance (P ＜ 0.01), and in schizonepeta
Ester group lifts unobvious compared to the cell survival rate of model control group, and its difference is not statistically significant (P ＞ 0.05).In addition,
Nepetalactone fluorobenzoate group significantly raises compared to the cell survival rate of vitamin E group and nepetalactone group, and its difference is equal
With pole conspicuousness statistical significance (P ＜ 0.01).This explanation nepetalactone fluorobenzoate has aobvious for neuronal cell
The protective effect of work.
The each group cell survival rate of table 1 compares
Compared with model control group,*P ＜ 0.01；With vitamin E group, #P ＜ 0.01；With nepetalactone group , $P ＜
0.01。
Claims (5)
1. nepetalactone or derivatives thereof is applied in the medicine for preparing treatment nerve degenerative diseases.
2. nepetalactone or derivatives thereof should in the medicine for preparing treatment nerve degenerative diseases according to claim 1
With, it is characterised in that described nepetalactone derivative is nepetalactone fluorobenzoate, and its structural formula is as follows：
3. nepetalactone or derivatives thereof should in the medicine for preparing treatment nerve degenerative diseases according to claim 1
With, it is characterised in that described nerve degenerative diseases are Parkinson's.
4. nepetalactone or derivatives thereof should in the medicine for preparing treatment nerve degenerative diseases according to claim 1
It is its raceme, stereoisomer, solvate with, it is characterised in that described nepetalactone or is metabolized as after entering body
The precursor compound of nepetalactone.
5. nepetalactone or derivatives thereof should in the medicine for preparing treatment nerve degenerative diseases according to claim 2
It is its raceme, stereoisomer, solvate or into machine with, it is characterised in that described nepetalactone fluorobenzoate
The precursor compound of nepetalactone fluorobenzoate is metabolized as after body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711114558.2A CN107823199A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone derivative in nerve degenerative diseases are treated |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711114558.2A CN107823199A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone derivative in nerve degenerative diseases are treated |
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| CN201711114558.2A Pending CN107823199A (en) | 2017-11-13 | 2017-11-13 | Application of the nepetalactone derivative in nerve degenerative diseases are treated |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1323793A (en) * | 2001-04-09 | 2001-11-28 | 南京中医药大学 | Schizonepeta lactone and its extraction process and use |
| CN102964321A (en) * | 2012-12-03 | 2013-03-13 | 南京中医药大学 | Nepetalactone fluorobenzoate, preparation technology and usage thereof |
-
2017
- 2017-11-13 CN CN201711114558.2A patent/CN107823199A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1323793A (en) * | 2001-04-09 | 2001-11-28 | 南京中医药大学 | Schizonepeta lactone and its extraction process and use |
| CN102964321A (en) * | 2012-12-03 | 2013-03-13 | 南京中医药大学 | Nepetalactone fluorobenzoate, preparation technology and usage thereof |
Non-Patent Citations (3)
| Title |
|---|
| BEIHUA BAO, ET AL.: "Design, Synthesis and Antiviral Activity Studies of Schizonepetin Derivatives", 《INT. J. MOL. SCI.》 * |
| CHARLOTTE WARREN-GASH, ET AL.: "Association between human herpesvirus infections and dementia or mild cognitive impairment: a systematic review protocol", 《BMJ OPEN》 * |
| JUDITH MIKLOSSY编辑: "《Handbook of lnfection and Alzheimer"s Disease》", 31 March 2017 * |
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Application publication date: 20180323 |