CN118141817A - Application of dopamine D3 receptor ligand in preparation of anti-Alzheimer disease drugs - Google Patents

Application of dopamine D3 receptor ligand in preparation of anti-Alzheimer disease drugs Download PDF

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Publication number
CN118141817A
CN118141817A CN202410408677.2A CN202410408677A CN118141817A CN 118141817 A CN118141817 A CN 118141817A CN 202410408677 A CN202410408677 A CN 202410408677A CN 118141817 A CN118141817 A CN 118141817A
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compound
dopamine
solution
medicament
alzheimer
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CN202410408677.2A
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Inventor
路承彪
李君美
叶真丽
马晓寅
杜靖之
胡琪琳
孙卓
周瑞
蒋海威
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Wuhan Saina Xingchen Technology Co ltd
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Wuhan Saina Xingchen Technology Co ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention belongs to the technical field of medicines and disease treatment, and particularly relates to application of a dopamine D3 receptor ligand derivative in preparation of an anti-Alzheimer disease medicine. The research result of the invention shows that the N-phenylpiperazine derivative HS-81 can obviously improve the learning and memory of a 5xFAD mouse. The study shows that the compound has the therapeutic potential of improving cognitive function and antagonizing AD.

Description

Application of dopamine D3 receptor ligand in preparation of anti-Alzheimer disease drugs
Technical Field
The invention belongs to the technical field of medicines and disease treatment, and particularly relates to application of a dopamine D3 receptor ligand derivative in preparation of an anti-Alzheimer disease medicine.
Background
Alzheimer's Disease (AD) is highly developed in the elderly. Cerebral rhythm disorders constitute the pathophysiological features of AD, which appear to be responsible for early cognitive decline. At present, neuroprotective drugs are timely administered before AD is converted into severe symptoms, and only symptoms can be delayed, so that the clinical test of the potential treatment method of AD is not ideal. At present, 320 clinical trials of drugs for AD hypothesis theory, including Abeta deposition, neuroinflammation, neurofibrillary tangle and the like, fail to be declared. Therefore, new ideas and strategies need to be developed with drugs.
The N-phenylpiperazine derivative has affinity and selectivity to dopamine D3 receptor (Dopamine D receptor, D3R), and can be used as a dopamine receptor ligand, which becomes a research hot spot of anti-AD drugs in recent years. However, the existing N-phenylpiperazine derivatives have the problem that the N-phenylpiperazine derivatives are not suitable for permeating the blood brain barrier when being applied. Thus, there is a need to develop a new dopamine D3 receptor ligand for use in products for the treatment of AD.
Disclosure of Invention
In order to solve the problem that the N-phenylpiperazine derivative AD-X is not suitable for permeating a blood brain barrier in the prior art, the research result shows that the N-phenylpiperazine derivative AD-X has a remarkable improving effect on the function of a hippocampal neuron network on the basis of the N-phenylpiperazine derivative AD-X synthesized in the early stage, and the N-phenylpiperazine derivative AD-X is possibly applied to the treatment of AD. Therefore, the invention provides application of the dopamine D3 receptor ligand derivative in preparing anti-Alzheimer disease medicines.
In order to achieve the above purpose, the invention adopts the following technical scheme:
The selective dopamine D3 receptor agonist directly acts on the DA energy nerve herniation posterior membrane and plays a role similar to dopamine. Because of high selectivity and few side reactions, the method becomes an important point for developing anti-parkinsonism medicaments. In recent years, research has found that dopamine receptor (DAR) is closely related to central nervous system diseases such as Parkinson's Disease (PD) and Alzheimer's Disease (AD), and has become an important target for preventing and treating PD and AD. The invention aims to provide the application of a dopamine D3 receptor ligand derivative in preparing an anti-Alzheimer disease drug. In the early research of the invention, based on a bamine D3 receptor ligand mother nucleus, an N-phenylpiperazine derivative AD-X is newly synthesized.
The structural formula of the compound AD-X is shown as follows:
the compound AD-X is an N-phenylpiperazine derivative.
According to the invention, the compound AD-X has the function of improving the learning and memory of senile dementia model mice. Based on this, the invention provides the use of compound AD-X in the preparation of a medicament against Alzheimer's disease.
The medicine takes compound AD-X as active ingredient and is assisted with pharmaceutically acceptable carrier. The preparation method of the conventional medicine in the field is used for preparing the medicine into a required medicine dosage form, and the conventional medicine dosage form comprises tablets, capsules, soft gelatin, spray, gel inhalants, oral preparations, suspension, medicinal granules, patches, ointments, pills, powder, injection, infusion solutions, freeze-dried injection, liposome injection, targeted administration injection, suppositories, sustained release preparations or controlled release preparations.
The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, and is selected from one or more of a filler, an adhesive, a disintegrating agent, a lubricant, a suspending agent, a wetting agent, a solvent, a surfactant or a flavoring agent.
Wherein the filler is one or more selected from starch, sucrose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose or glucose.
The adhesive is one or more selected from cellulose derivatives, alginate, gelatin or polyvinylpyrrolidone.
The disintegrating agent is one or more selected from microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or crosslinked sodium carboxymethyl cellulose.
The lubricant is one or more selected from stearic acid, polyethylene glycol, calcium carbonate, sodium bicarbonate, micro silica gel, talcum powder and magnesium stearate.
The suspending agent is one or more selected from micropowder silica gel, cera flava, cellulose and solid polyethylene glycol.
The wetting agent is one or more selected from glycerol, tween-80, ethoxylated hydrogenated castor oil or lecithin.
The solvent is selected from ethanol, liquid polyethylene glycol, isopropanol, tween-80, glycerol, propylene glycol or vegetable oil.
After knowing the use of the compound AD-X, a variety of methods well known in the art can be employed to administer the compound AD-X or their pharmaceutical compositions to a mammal. Including but not limited to: subcutaneous injection, intramuscular injection, transdermal administration, topical administration, implantation, sustained release administration, and the like.
The effective content of the compound AD-X in the medicine prepared by the invention is 95.5-95.7%. The preferred effective content is 95.6%.
On the basis, the invention also provides an anti-Alzheimer disease drug, and the drug is a solution.
Specifically, the solution consists of the following raw materials: the compound AD-X solution comprises a compound AD-X, a solvent and a cosolvent, wherein the concentration of the compound AD-X in the solution is 0.56-0.78 mg/mL.
The solvent is any one of DMSO, DMF and cyclohexanol cyclohexanone; the cosolvent is any one of ethanol, liquid polyethylene glycol, isopropanol, tween-80, glycerol and vegetable oil.
Wherein the vegetable oil is one or more selected from soybean oil, castor oil, peanut oil, blend oil and the like.
Compared with the prior art, the invention has the following beneficial effects:
The invention provides application of a dopamine D3 receptor ligand derivative in preparing an anti-Alzheimer disease drug, and provides a novel anti-Alzheimer disease method. In the early research of the invention, based on a bamine D3 receptor ligand mother nucleus, an N-phenylpiperazine derivative AD-X is newly synthesized. On the basis of early-stage research, a classical senile dementia model mouse (5 xFAD) is adopted as a research object, the influence of the compound AD-X on the Y maze of the mouse and the identification of a new object is directly observed through continuous intraperitoneal injection of the compound AD-X, whether the related index changes or not is recorded by computer software in real time, the collected information is more real, and the research result is reliable. The research results of the invention prove that: the compound AD-X has new pharmacological action and can improve the learning and memory potential of 5xFAD mice. The N-phenylpiperazine derivative AD-X has a remarkable improvement effect on the function of the hippocampal neural network, which indicates that the N-phenylpiperazine derivative AD-X can be possibly applied to the treatment of AD.
Drawings
FIG. 1 is a schematic diagram of a Y-maze test of the present invention;
FIG. 2 is a Y-maze test of the present invention, wherein A is the percentage of new arm entry before and after dosing for AD mice; b is that for AD mice, the total distance of movement before and after drug administration has no obvious difference;
FIG. 3 is a diagram illustrating the behavior of new object recognition in the present invention;
FIG. 4 is a novel object recognition behavioral experiment in accordance with the present invention, wherein A is the effect of compound AD-X on the AD mouse NOR novel object recognition index; b is the influence of the compound AD-X on the movement distance of the AD mice.
Detailed Description
The present invention will now be described in detail with reference to the drawings and specific examples, which should not be construed as limiting the invention. Unless otherwise indicated, the technical means used in the following examples are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise indicated.
The following are the experimental animals and experimental materials involved in the examples:
1. Experimental animal
C57BL/6WT mice were purchased from Jiangsu Jixiaokang Biotech Co.
5XFAD mice were purchased from Jiangsu Jixiaokang Biotech Co.
2. Experimental materials
The behavioural experimental device was purchased from Anhua Zhenghua biological instrument & devices Co., ltd.
3. Compounds AD-X
The compound AD-X used in the invention is an N-phenylpiperazine derivative and a dopamine D3 receptor ligand derivative, and the structural formula is as follows:
the compound AD-X used in the invention is synthesized autonomously in the laboratory.
The specific synthesis process of the compound AD-X is shown in the application number: chinese patent CN 201810040879.0.
Example 1
To further illustrate the scheme of the use of the dopamine D3 receptor ligand derivatives provided by the invention in the preparation of anti-alzheimer's disease drugs, we use the dopamine D3 receptor ligand derivatives; the compound AD-X was studied as follows:
According to the invention, 9 5XFAD mice are selected as study objects for each component, and the 9 5XFAD mice are divided into 3 groups of 3 mice each.
The specific grouping and processing of each group is as follows:
(1) Blank control group: no special treatment is done.
(2) Solvent control group: sesame oil (except for the solvent without AD-X) was injected intraperitoneally, and 200uL of each animal was administered at a dose of 5mg/kg. Injection was continued for 5 days.
(3) Study group: the compound AD-X solution is injected into the abdominal cavity, and the injection amount is as follows: 5mg/kg mice, 5 days of continuous injection.
The preparation method of the compound AD-X solution comprises the following steps:
Preparing mother solution: 13.75mg of compound AD-X was dissolved in 1100 mu LDMSO solution, mother liquor concentration: 12.5mg/ml. Compound AD-X was a white powder.
Method for preparing compound AD-X solution for in vivo injection: taking 1100 mu L of the mother liquor, and adding the mother liquor into 20.9mL of sesame oil.
The following behavioural indices were observed for all three groups of mice: y maze experiment: the percentage of the novel arm entering the arm before and after the administration and the total movement distance are obviously different; new object identification experiment: the cognitive index and the total distance of movement before and after the administration have obvious differences. The specific studies were as follows:
1. Y-Maze (Y-Maze)
For three identical arms: y maze formed by 30cm x 8cm x 15cm long x width x height, each arm included angle is 120 degrees, a movable partition board is placed in the middle, paper with different colors is stuck in each arm of the maze, and vision is marked. The arm where the mice were placed into the maze at the beginning of the experiment was called the starting arm (start arm), the first stage of the experimental training period was blocked by the baffle, the second stage of the testing period was the new arm (novel arm), and the mice were allowed to freely access the starting arm and other arms (other arm) throughout the experiment.
The experimental details were as follows: in the training period (first stage), the mouse is placed on the starting arm, the free movement is finished after 5min, the test period (second stage) is started after 60min, the novel arm partition plate is opened, the mouse is still placed on the starting arm, the free movement is finished after 5min, the camera is arranged at the position 1.5m above the maze, and the whole process is recorded.
The schematic diagram of the Y-maze experiment is shown in FIG. 1.
The experimental results are shown in FIG. 2.
As can be seen from fig. 2, after administration, the AD mice significantly increased the percentage of new walls entered, with no significant difference in total distance moved before and after administration.
2. New object identification experiment (Novel object recognition test NOR)
New object recognition experiments the cognitive memory of animals is assessed by the length of time that the experimental animals explore a familiar object and a new strange object. The device is an open field experimental device shown in figure 3.
The experimental details were as follows:
Adaptation period (first stage); without placing any object, the mice were free to move in the experimental set-up for 5 minutes.
Familiarity period (second stage): 2 identical objects were placed at positions in the experimental set-up, the objects being about 10cm from both sidewalls. From equidistant from the object, the mice were placed back into the device, and recorded for 5min.
Test period (third stage); after 60 minutes from the completion of the second phase, one of the two identical objects was replaced with a different object and placed in the apparatus, again from the equidistant point from the object, the mice were placed back to the object and recorded for 5 minutes.
The experimental results are shown in FIG. 4.
As can be seen from fig. 4, after administration, the cognitive index of AD mice was significantly increased, and there was no significant difference in total distance between exercise before and after administration.
The above two behavioural results indicate that: the compound AD-X can enhance the cognitive memory of AD mice.
The invention provides application of a dopamine D3 receptor ligand derivative in preparing an anti-Alzheimer disease drug, and provides a novel anti-Alzheimer disease method. The medicine takes the dopamine D3 receptor ligand derivative as an active ingredient and is assisted with a pharmaceutically acceptable carrier.
The invention provides a medicine for resisting Alzheimer disease, which takes a dopamine D3 receptor ligand derivative as an active ingredient, and can be prepared into oral dosage forms, injection dosage forms, inhalation dosage forms and other pharmaceutical dosage forms. Specific pharmaceutical dosage forms include injection, solution, powder, tablet, pill, aerosol, capsule, and emulsifier. The medicine is prepared by matching the dopamine D3 receptor ligand derivative with different carriers according to different dosage forms and processing the dopamine D3 receptor ligand derivative into a dosage form for animals through a preparation process of the corresponding dosage form.
The carrier is a conventional pharmaceutical carrier in the pharmaceutical field, and comprises any one of ethanol, liquid polyethylene glycol, isopropanol, tween-80, glycerol, sesame oil, water, saline, buffer solution, micro silica gel, cellulose, stearic acid, cellulose derivatives, starch, sucrose and lactose.
The preparation method is characterized in that the medicine can be prepared into a proper dosage form according to actual needs, and the medicine can be prepared according to a corresponding preparation method of a corresponding medicine dosage form.
The effect of the solution is described below by way of example, and the following is a specific study:
a dopamine D3 receptor ligand derivative; a solution of compound AD-X as active ingredient, consisting of: compound AD-X13.75 mg, DMSO 1.1mL, sesame oil 20.9mL.
The preparation method of the solution comprises the following steps:
Preparing mother solution: 13.75mg of compound AD-X was dissolved in 1100 mu LDMSO solution, mother liquor concentration: 12.5mg/ml. Compound AD-X was a white powder.
Method for preparing compound AD-X solution for in vivo injection: taking 1100 mu L of the mother liquor, and adding the mother liquor into 20.9mL of sesame oil.
The curative effect of the 5XFAD mice is detected by the prepared solution, and the specific steps are as follows:
The specific grouping and processing of each group is as follows:
(1) Blank control group: no special treatment is done.
(2) Solvent control group: sesame oil (except for the solvent without AD-X) was injected intraperitoneally, and 200uL of each animal was administered at a dose of 5mg/kg. Injection was continued for 5 days.
(3) Study group: the compound AD-X solution is injected into the abdominal cavity, and the injection amount is as follows: 5mg/kg mice, 5 days of continuous injection.
Specific study methods were the same as the above examples, including the following behavioral indicators for all three groups of mice: y maze experiment: the percentage of the novel arm entering the arm before and after the administration and the total movement distance are obviously different; new object identification experiment: the cognitive index and the total distance of movement before and after the administration have obvious differences.
The study results were: after administration of mice from the study group, the percentage of AD mice entering the novel wall was significantly increased and the cognitive index of AD mice was significantly increased.
From the above results, it can be derived that: the invention provides a dopamine D3 receptor ligand derivative: the solution agent with the compound AD-X as an active ingredient has the effect of antagonizing Alzheimer disease. The result shows that the dopamine D3 receptor ligand derivative provided by the invention has the capability of antagonizing Alzheimer's disease, and can provide a material basis for preparing medicines for treating and preventing Alzheimer's disease.
It should be noted that, when the claims refer to numerical ranges, it should be understood that two endpoints of each numerical range and any numerical value between the two endpoints are optional, and the present invention describes the preferred embodiments for preventing redundancy.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. It is therefore intended that the following claims be interpreted as including the preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims (10)

1. Use of dopamine D3 receptor ligands and derivatives thereof in the preparation of a medicament against alzheimer's disease.
2. The use according to claim 1, wherein the dopamine D3 receptor ligand derivative is a compound AD-X having the structural formula:
3. the use according to claim 2, wherein the medicament comprises compound AD-X as active ingredient, in combination with a pharmaceutically acceptable carrier.
4. The use according to claim 3, wherein the pharmaceutical dosage form comprises an oral dosage form, an injectable dosage form, an inhalable dosage form.
5. The use according to claim 4, wherein the medicament comprises an injection, a solution, a powder, a tablet, a pill, an aerosol, a capsule, an emulsifier.
6. The use according to claim 3, wherein the effective content of the compound AD-X in the medicament is 95.5-95.7%.
7. The use according to claim 3, wherein the pharmaceutical co-carrier comprises one or more of a filler, a binder, a disintegrant, a lubricant, a suspending agent, a wetting agent, a solvent, a surfactant or a flavoring agent.
8. An anti-alzheimer's disease medicament, characterized in that the medicament is a solution.
9. The anti-alzheimer's disease agent according to claim 8, wherein said solution is composed of the following raw materials: the compound AD-X solution comprises a compound AD-X, a solvent and a cosolvent, wherein the concentration of the compound AD-X in the solution is 0.56-0.78 mg/mL.
10. The anti-alzheimer's disease drug according to claim 9, wherein the solvent is any one of DMSO, DMF, cyclohexanol cyclohexanone; the cosolvent is any one of ethanol, liquid polyethylene glycol, isopropanol, tween-80, glycerol and vegetable oil.
CN202410408677.2A 2024-04-07 2024-04-07 Application of dopamine D3 receptor ligand in preparation of anti-Alzheimer disease drugs Pending CN118141817A (en)

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CN202410408677.2A CN118141817A (en) 2024-04-07 2024-04-07 Application of dopamine D3 receptor ligand in preparation of anti-Alzheimer disease drugs

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