CN105434439B - A kind of partial agonist of d2 dopamine receptor inhibits the application on near-sighted drug and its application method preparing - Google Patents
A kind of partial agonist of d2 dopamine receptor inhibits the application on near-sighted drug and its application method preparing Download PDFInfo
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- CN105434439B CN105434439B CN201510763649.3A CN201510763649A CN105434439B CN 105434439 B CN105434439 B CN 105434439B CN 201510763649 A CN201510763649 A CN 201510763649A CN 105434439 B CN105434439 B CN 105434439B
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- 208000001491 myopia Diseases 0.000 title claims abstract description 45
- 239000004031 partial agonist Substances 0.000 title claims abstract description 20
- 101150049660 DRD2 gene Proteins 0.000 title claims abstract description 19
- 229940079593 drug Drugs 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title abstract description 11
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 33
- 230000004379 myopia Effects 0.000 claims abstract description 31
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 5
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 abstract description 30
- 229960003638 dopamine Drugs 0.000 abstract description 15
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 239000000556 agonist Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 8
- 210000001508 eye Anatomy 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 206010021703 Indifference Diseases 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 230000004323 axial length Effects 0.000 description 3
- 239000012155 injection solvent Substances 0.000 description 3
- 230000004423 myopia development Effects 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 2
- 210000001110 axial length eye Anatomy 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 229940096895 Dopamine D2 receptor agonist Drugs 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002288 dopamine 2 receptor stimulating agent Substances 0.000 description 1
- 229940126889 dopamine receptor partial agonist Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000004402 high myopia Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000000162 simple eye Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
Classifications
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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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A kind of partial agonist of d2 dopamine receptor inhibits the application on near-sighted drug and its application method preparing, and passes through and applies dopamine D 2 R-portion agonist Aripiprazole（Aripiprazole）Stablize effect of the d2 dopamine receptor in myopia, Aripiprazole inhibits the extension of vitreous chamber and axis oculi during ultrastructure in form deprivation myopia, to inhibit the formation of zoopery myopia.
Description
Technical field
The present invention relates to myopia fields, and in particular to a kind of partial agonist of d2 dopamine receptor inhibits preparing
Application on near-sighted drug and its application method.
Background technology
Dopamine (dopamine, DA) is a kind of neurotransmitter on retina, we and forefathers have found in zoopery
It was found that DOPAMINE CONTENT IN RABBIT is reduced in retina in near-sighted forming process, increased again in convalescence and be restored to normal level, changed
Rule lapses to that degree is highly consistent with ultrastructure in form deprivation myopia, and dopamine is prompted to take part in the formation of myopia.While the study found that
The non-selective agonist apomorphine of dopamine receptor（APO）It can inhibit the progress of chicken and monkey myopia, further support
Inhibiting effect of the dopamine to development of myopia.Epidemiological survey in recent years shows that outdoor activities can reduce teenager
The occurrence and development of myopia, may be related with outdoor stronger intensity of illumination, and the synthesis of dopamine and secretion are illuminated by the light,
Therefore dopamine may play a crucial role wherein.
Our early-stage studies the result shows that, selective dopamine D 2 receptor agonist can promote the spontaneous height of Albino guinea pig
Myopia, while the progress of the ultrastructure in form deprivation myopia of mouse and three color cavys can be promoted；Conversely, selective dopamine D 2 receptor is short of money
Anti-agent can inhibit the spontaneous high myopia of Albino guinea pig simultaneously and the progress of the ultrastructure in form deprivation myopia of mouse and three color cavys.
Demonstrate the hair that exciting d2 dopamine receptor can promote near-sighted occurrence and development and antagonism d2 dopamine receptor then inhibits myopia
Hair tonic exhibition.Simultaneously we have found that compared with wild type, d2 dopamine receptor KO mouse dioptrics are developed to be deviated toward long sight direction, shape
Feel that the effect for depriving myopia is partly inhibited, this also prompts D2 antagonisms to can inhibit near-sighted formation.Therefore, dopamine D 2 R is to close
Depending on occurrence and development play vital regulating and controlling effect.
Aripiprazole is the partial agonist of a kind of d2 dopamine receptor, also referred to as dopamine stabilizers.With it is complete
Full agonist is compared, and the binding ability of partial agonist and receptor is stronger, but intrinsic activity is not as good as full agonist.Swash part
Dynamic agent can not only be used as functional agonist, but also can be used as functional antagonist, this depends primarily on peripheral nerve and passs
The level of matter.Under conditions of lacking full agonist, partial agonist shows functional agonism, thus and receptor
In conjunction with generation response.And under the conditions of existing for full agonist, partial agonist shows that functional antagonism acts on again, to
It is combined with receptor and reduces response.Therefore, it is acted on using the unique pharmacological of Aripiprazole, dopamine D 2 R can be stablized and existed
Effect in myopia, to come inhibit myopia formation.
Up to the present it there is no discovery to play the role of d2 dopamine receptor partial agonist to report myopia.Therefore, we
Guess, can be by stablizing effect of the d2 dopamine receptor in myopia is formed, to reach the mesh for intervening development of myopia
's.
Invention content
In order to solve the deficiencies in the prior art, the present invention provides a kind of partial agonists of d2 dopamine receptor to prepare
Inhibit the application on near-sighted drug and its application method.
The technical solution that the present invention uses is：A kind of partial agonist of d2 dopamine receptor is near-sighted in preparation inhibition
Application on drug.
The partial agonist is Aripiprazole（Aripiprazole）.
The Aripiprazole（Aripiprazole）Dosage on inhibiting myopia is 5-15 mg/kg/day.
The Aripiprazole（Aripiprazole）Dosage on inhibiting myopia is 10mg/kg/day.
A kind of a kind of application method of the partial agonist of d2 dopamine receptor comprising following steps：Black
Under dark condition, by Aripiprazole（Aripiprazole）It is dissolved in 20% dimethyl formamide solution（DMF）In, adjust PH with acetic acid
It to 5 ~ 6, and makes it completely dissolved, is injected intraperitoneally under dark condition.
The beneficial effects of the invention are as follows：The present invention provides a kind of partial agonists of d2 dopamine receptor to prepare inhibition
Application on near-sighted drug and its application method, by applying dopamine D 2 R-portion agonist Aripiprazole
（Aripiprazole）Stablize effect of the d2 dopamine receptor in myopia, Aripiprazole inhibits form-deprivation close
Depending on the extension of vitreous chamber and axis oculi in the process, to inhibit the formation of zoopery myopia.
Description of the drawings
Fig. 1 is this experimental eye and Second eye diopter differential chart.
Fig. 2 is experimental eye and Second eye vitreous cavity depth differential chart.
Fig. 3 is experimental eye and Second eye axiallength differential chart.
Specific implementation mode
It is four week old C57BL/6 mouse by experimental animal.It is carried out using hemispherical opaque-plastic eyeshade covering method simple eye
Form deprivation（FDM）Surrounding, Second eye are own control eye.Form deprivation myopia various dose is given once daily simultaneously
Aripiprazole is injected intraperitoneally.Animal is randomly divided into 4 groups：Simple form deprivation group（FD）, form deprivation solvent group（FD-
Vehi）, form deprivation low dose group（FD-APZ-1 gives Aripiprazole dosage 1mg/kg/day）, the high agent of form deprivation
Amount group（FD-APZ-10 gives Aripiprazole dosage 10 ± 5mg/kg/day）.Test it is forward and backward respectively measure diopter,
The eyeballs biological parameter such as corneal curvature, axis oculi.
Aripiprazole is dissolved in 20% dimethyl formamide solution（DMF）In, PH is adjusted to 5 ~ 6 with acetic acid, and makes it
It is completely dissolved.Dosage has been selected after the specific biological effect after considering drug effective dose 50 and its being combined with receptor
Respectively the APZ solution of 1 mg/kg and 10mg/kg, solvent group give isometric DMF solution.1 hour after daily morning bright light
It is interior that isometric drug or solvent is injected intraperitoneally.To avoid drug from decomposing in light, all drugs and solvent injection process are unified in
It is carried out in darkroom.
Biological parameter difference not significantly (P before experiment in each group and between group>O.05).After testing four weeks, simplex
Group is deprived in feel and form deprivation solvent group has all induced apparent myopia amount（FD：11.38 ± 0.77D；FD-Vehi：10.05
± 0.99D), the Aripiprazole of high dose 10mg/kg/day inhibits about 50% ultrastructure in form deprivation myopia (FD-APZ-10
VS FD-Vehicle：5.94 ± 0.98D VS 10.05 ± 0.99D, P<0.001, one-way analysis of variance), and low dosage
Effect unobvious of the Aripiprazole of 1mg/kg/day to mouse ultrastructure in form deprivation myopia（FD-APZ-1 VS FD-
Vehicle：9.91 ± 0.99D VS 10.05 ± 0.99D, P>0.05）.Equally, it is found that high dose Aripiprazole is inhibited
The extension of vitreous chamber and axis oculi during ultrastructure in form deprivation myopia.Therefore, intraperitoneal injection Aripiprazole can portion
Divide the formation for inhibiting mouse ultrastructure in form deprivation myopia.
Experimental result is as shown in Figure 1, Figure 2, Figure 3 shows：
Fig. 1 is experimental eye and Second eye diopter differential chart." difference " refers to experimental eye and joins with Second eye diopter or axis oculi
Several differences；" * " indicates P< 0.05.After testing four weeks, simple form deprivation group and form deprivation solvent group form near-sighted amount
Indifference illustrates injection solvent on form deprivation without influence.Form deprivation high dose group forms myopia amount and is less than solvent group, explanation
Dopamine D 2 partial agonist Aripiprazole can inhibit the formation of ultrastructure in form deprivation myopia.
Fig. 2 is experimental eye and Second eye vitreous cavity depth differential chart.After testing four weeks, simple form deprivation group and shape are felt
It deprives solvent group and forms vitreous cavity depth indifference, illustrate injection solvent on the vitreous cavity depth of form deprivation without influence.
The vitreous cavity depth that form deprivation high dose group is formed is less than solvent group, illustrates dopamine D 2 partial agonist
Aripiprazole can inhibit the extended formation of ultrastructure in form deprivation myopia vitreous chamber.
Fig. 3 experimental eyes and Second eye axiallength differential chart.After testing four weeks, simple form deprivation group and form deprivation are molten
Agent group forms axiallength indifference, illustrates injection solvent on form deprivation axiallength without influence.Form deprivation high dose group
The axiallength of formation is less than solvent group, illustrates that dopamine D 2 partial agonist Aripiprazole can inhibit form-deprivation close
Depending on the extended formation of axis oculi.
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (3)
1. a kind of partial agonist of d2 dopamine receptor is preparing the application inhibited on near-sighted drug, which is characterized in that described
Partial agonist be Aripiprazole（Aripiprazole）.
2. a kind of partial agonist of d2 dopamine receptor according to claim 1 answering on preparing the near-sighted drug of inhibition
With, which is characterized in that the Aripiprazole（Aripiprazole）Dosage on inhibiting myopia is 5-15 mg/kg/day.
3. a kind of partial agonist of d2 dopamine receptor according to claim 1 answering on preparing the near-sighted drug of inhibition
With, which is characterized in that the Aripiprazole（Aripiprazole）Dosage on inhibiting myopia is 10mg/kg/day.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1179979A (en) * | 1996-10-03 | 1998-04-29 | 株式会社Lg化学 | Ophithalmic formulation for treating myopia comprising dopamine agonist and cyclodextrin |
| CN1225093A (en) * | 1996-07-08 | 1999-08-04 | 诺瓦提斯公司 | Benzo[g] quinoline derivatives |
| WO2000054773A1 (en) * | 1999-03-12 | 2000-09-21 | Nitromed, Inc. | Dopamine agonists in combination with nitric oxide donors, compositions and methods of use |
-
2015
- 2015-11-11 CN CN201510763649.3A patent/CN105434439B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1225093A (en) * | 1996-07-08 | 1999-08-04 | 诺瓦提斯公司 | Benzo[g] quinoline derivatives |
| CN1179979A (en) * | 1996-10-03 | 1998-04-29 | 株式会社Lg化学 | Ophithalmic formulation for treating myopia comprising dopamine agonist and cyclodextrin |
| WO2000054773A1 (en) * | 1999-03-12 | 2000-09-21 | Nitromed, Inc. | Dopamine agonists in combination with nitric oxide donors, compositions and methods of use |
Non-Patent Citations (2)
| Title |
|---|
| An updated view on the role of dopamine in myopia;Marita Feldkaemper等;《Experimental eye research》;20130219;第114卷;106-119 * |
| 多巴胺受体部分激动剂阿立哌唑药理作用与临床应用;吉中孚;《中国新药杂志》;20051231;第14卷(第5期);629-631 * |
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