WO2008000142A1 - Agoniste du transporteur de la dopamine et ses utilisations - Google Patents

Agoniste du transporteur de la dopamine et ses utilisations Download PDF

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WO2008000142A1
WO2008000142A1 PCT/CN2007/001839 CN2007001839W WO2008000142A1 WO 2008000142 A1 WO2008000142 A1 WO 2008000142A1 CN 2007001839 W CN2007001839 W CN 2007001839W WO 2008000142 A1 WO2008000142 A1 WO 2008000142A1
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dopamine
dopamine transporter
group
disease
agonist
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PCT/CN2007/001839
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Chinese (zh)
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Lihe Guo
Gang Zhao
Mingmin Xu
Xuesong Wang
Shaoyun Zang
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Cell Star Bio-Technologies Co., Limited
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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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to the field of biomedicine, and more particularly, to a class of dopamine transporter agonists and their use. Background technique
  • neurological diseases such as anxiety disorders, mood disorders, schizophrenia, personality disorders, psychosexual disorders > substance abuse And drug abuse and dependence affect people of all ages, and the duration of these diseases varies from weeks to decades.
  • Dopamine is a major catecholamine neurotransmitter in the mammalian brain that controls many functions such as exercise, cognition, emotion, positive reinforcement, feeding, and endocrine regulation. Dopamine accounts for 80% of the brain's catecholamine neurotransmitters and is one of the most important neurotransmitters in the mammalian central nervous system. It plays a key regulatory role in the physiological and mental health of the human body.
  • nerve impulse transmission Under normal physiological conditions, the process of nerve impulse transmission is as follows: When nerve cells transmit nerve impulses, neurotransmitters are released from neurons to synaptic spaces, and neurotransmitters bind to corresponding receptors on postsynaptic, resulting in physiological effects. At the same time, neurotransmitters are inactivated by different mechanisms. There are two main ways in which neurotransmitters are inactivated. One is the rapid metabolism of neurotransmitters to inactive substances; the other is the neurotransmitter that re-uptakes synaptic clefts through presynaptic membranes or glial cells. The re-uptake of neurotransmitters can be used repeatedly by neurons. The way of dopaminergic neurons belongs to the latter.
  • DAT dopamine transporter
  • Dopaminergic hyperfunction (excessive dopamine secretion or high sensitivity of dopamine receptors in the brain) leads to disorder of dopaminergic neuroregulation, which is the main pathogenesis and important pathological links of many diseases, such as drug addiction and schizophrenia. , anxiety, emotional affliction, Drug abuse and dependence, Tourette's syndrome, muscle weakness, tardive dyskinesia, etc.
  • the object of the present invention is to provide a class of dopamine transporter agonists which can regulate the transport of dopamine by promoting the transport function of dopamine transporters, maintain the balance of extracellular dopamine concentration, and can be used for the preparation of psychotic diseases and neurological diseases. medicine.
  • a flavonoid or a derivative thereof for the preparation of a pharmaceutical composition as a dopamine transporter agonist, or for the preparation of a medicament for treating a divine or neurological disease.
  • the agonist is an agonist of dopamine transporter reuptake.
  • the mental disease or neurological disease is a mental disease or a neurological disease caused by hyperparaceptive hyperactivity.
  • the flavonoid compound is selected from the group consisting of: apigenin, luteolin, quercetin, myricetin, poplarin, soybean aglycone, wogonin, baicalein, Genistein, morin, marigold, hesperetin, buckthorn gold, rhamnosin, or a combination thereof.
  • the flavonoid is selected from the group consisting of: luteolin, apigenin, quercetin, soyin, or a combination thereof.
  • the flavonoid is luteolin.
  • the mental disease or neurological disease is a dopaminergic hyperfunction disorder.
  • the mental or neurological disease is selected from the group consisting of: an addiction disorder, an anxiety disorder, Alzheimer's syndrome, anorexia nervosa, schizophrenia, Parkinson's syndrome, Insomnia, drug abuse and dependence, vomiting, irritable bowel syndrome, menopausal syndrome, Wilson's disease, chorea, demyelinating disease, mania, obsessive-compulsive disorder, or Tourette's syndrome.
  • the psychotic or neurological disorder is selected from the group consisting of: an addiction disorder, schizophrenia, or drug abuse and dependence.
  • the addictive disease is an opioid addiction.
  • the opioid comprises, but is not limited to, opioid, morphine, heroin, cocaine, dulamine, methadone, amphetamine, wherein morphine, or cocaine is preferred.
  • a method of determining a candidate drug useful for treating a psychiatric or neurological disorder comprising the steps of:
  • the dopamine transport amount of the test group indicates that the candidate substance is an agonist of the dopamine transporter, and thus can be used as a drug candidate for treating a mental disease or a neurological disease.
  • the method further includes the following steps:
  • step (3) administering a candidate substance of the agonist which has been shown to be a dopamine transporter obtained in the step (2) to a model animal of a mental disease or a neurological disease of a non-human mammal, and observing the behavior of the model animal To determine whether the symptoms of their treatment for mental illness or neurological disease have improved,
  • candidate substances which significantly improve the symptoms of treating mental illness or neurological diseases in model animals are candidates for the treatment of psychiatric diseases or neurological diseases.
  • the animal model is a mouse, a rat, or a monkey.
  • step (3) the following behavior or symptoms of the model animal are included in step (3) including, but not limited to, abnormal posture, irritation, gnaw, tearing, diarrhea, salivation or weight loss, or a combination thereof.
  • a dopamine transporter agonist is provided, wherein the dopamine transporter agonist is capable of specifically promoting dopamine transporter uptake of dopamine and said dopamine transporter agonist is used as a therapeutic psychotropic A drug for a disease or a neurological disease.
  • a dopamine transporter agonist for the preparation of a pharmaceutical composition for the treatment of a psychiatric or neurological disorder.
  • the agonist is a flavonoid. More preferably, the agonist is selected from the group consisting of luteolin.
  • a method of treating a psychiatric or neurological condition comprising: administering an effective amount of a flavonoid or a derivative thereof to a subject in need of treatment.
  • the present invention provides a pharmaceutical composition for treating a psychiatric disease or a neurological disease, the pharmaceutical composition comprising an effective amount of a flavonoid compound or a derivative thereof, and a pharmaceutically acceptable carrier .
  • the pharmaceutical composition comprises:
  • Flavonoids or derivatives thereof 5-10 parts by weight
  • a pharmaceutically acceptable carrier 80-150 parts by weight
  • the total content of the flavonoid compound or its derivative is from 0.1 to 20% by weight based on the total weight of the pharmaceutical composition. .
  • the pharmaceutical composition contains at least one flavonoid compound selected from the group consisting of apigenin, luteolin, quercetin, myricetin, poplarin, and soybean aglycone. , baicalein, baicalein, genistein, morin, marigold, lysin, buckthorn gold, or buckthorn.
  • Figure 1 shows the extraction and separation of sz ethanol extract into four parts, namely petroleum ether (szi), chloroform ( ⁇ 2), ethyl acetate (SZ3) and n-butanol (SZ4), which are at 10 ⁇ g/ml.
  • szi petroleum ether
  • ⁇ 2 chloroform
  • SZ3 ethyl acetate
  • SZ4 n-butanol
  • Figure 2 shows the effect of 'SZ3' divided into multiple sites on the polyacrylamide gel, which have an effect on the uptake of dopamine at a concentration of 10 g/ml.
  • Figure 3 shows the uptake of dopamine by apigenin (SZ91) at concentrations of 1 ⁇ g/ml and 10 ⁇ g/ml.
  • Figure 4 shows the effect of different concentrations of luteolin (SZ92) on dopamine uptake.
  • Figure 5 shows the effect of purine acetylated SZ92' on dopamine uptake at a concentration of 10 ⁇ g/ml.
  • Figure 6 shows the activity of SZ92 on dopamine uptake.
  • Figure 1 shows the effect of SZ91 and SZ92 on the viability of glutamate transporters in COS-7 cells.
  • Figure 8 shows the effects of soybean aglycone, quercetin, genistein, and apigenin on the activity of glutamate transporters in COS-7 cells.
  • Figure 9 shows the score of Yanagida's score for withdrawal symptoms in the morphine addiction modeling of rats.
  • Figure 10 shows the scores of Yanagida Eiji who had withdrawal symptoms when the rats were treated with morphine addiction.
  • Figure 11 shows a comparison of the preference times of mice in each side of the white box.
  • Figure 12 shows a comparison of the pain sensation period (the hind limb time) of each group of mice.
  • Figure 13 shows a comparison of the total number of grids traversed within 2 hours for each test group of animals.
  • the present inventors After long-term research and experiment, the present inventors first proposed the dopamine transporter agonism theory and proved that Dopa Amine transporters can be agonized, and this agonistic effect can serve as a new target for the treatment of psychiatric and neurological diseases. Moreover, the inventors obtained a class of dopamine transporter agonists which can significantly promote the transport of dopamine transporters or uptake of dopamine by drug screening. The present invention has been completed based on the above research results.
  • the uptake and transport of dopamine by dopamine transporters can be stimulated, the uptake of synaptic interstitial dopamine can be enhanced, the extracellular dopamine concentration can be regulated, the dopamine homeostasis can be maintained in the synaptic cleft, and the postsynaptic dopa neurons can be reduced.
  • Excitability. Stimulation of the transport of dopamine transporters can be achieved using dopamine transporter agonists.
  • the "dopamine transporter agonist” includes all substances which enhance the uptake and transport function of dopamine transporter to dopamine, which are capable of fully or partially stimulating dopamine transporter transport or uptake of dopamine. More preferably, the "dopamine transporter agonist” is a flavonoid compound, a derivative thereof or the like.
  • the term "flavonoid” refers to a generic term for a class of compounds in which two benzene rings are joined by a three carbon chain to form a C6-C3-C6 basic skeleton, and the structural formula is as in formula (I) or formula. ( ⁇ ) shows:
  • the flavonoids include, but are not limited to, apigenin (also referred to herein as SZ91), luteolin (also referred to herein as SZ92), quercetin. , myricetin, chrysin, dadzein, wogonin, baicalein, genistein, morin, marigold (quercetagetin), hesperetin, rhamnazin, rhamnetin.
  • the flavonoid compound is selected from the group consisting of luteolin, apigenin, quercetin, or soybean aglycone; wherein the luteolin has a structure represented by formula (III); The substance has the structure shown in formula (IV):
  • the flavonoid compound is luteolin.
  • the dopamine transporter agonist may be present in the form of a pure flavonoid or a derivative thereof; or may be a mixture or extract containing a flavonoid compound or a derivative thereof (for example, extractable from a traditional Chinese medicine)
  • the form exists; or it may be in the form of a Chinese medicinal material containing a flavonoid compound or a derivative thereof or an active site of a traditional Chinese medicine.
  • the dopamine transporter agonist promotes the dopamine transporter to dopamine uptake, but has no effect or effect on other transporters (e.g., y-aminobutyrate transporter). This indicates that the dopamine transporter agonist is specific for promoting dopamine transporter uptake function.
  • the mental diseases and neurological diseases include, but are not limited to, the following diseases: Addictive diseases
  • the addictive disease is an opioid drug addiction.
  • the opioids include, but are not limited to, opioids, morphine, heroin, cocaine, dulamine, methadone, amphetamine, with morphine, or cocaine being preferred. ⁇
  • the dopamine protein agonist of the present invention enables the body to reduce the withdrawal symptoms caused by opioid addiction, thereby achieving a good effect of treating the addiction and abuse of opioids. Its mechanism of action is: The use of dopamine transporter agonists to promote dopamine transporter dopamine uptake in the synaptic cleft, thereby reducing the dopamine receptor dopamine receptor agonism and attenuating the dopamine neuron excitation. Therefore, it has a corrective effect on the abnormal hyperactivity of the dopaminergic nerve (reward effect system) caused by opioid addiction.
  • the dopamine protein agonist of the present invention enables the body to reduce symptoms of schizophrenia.
  • Schizophrenia is associated with increased dopamine function in the brain.
  • Dopamine transporter agonists promote the dopamine uptake of dopamine transporters in the synaptic cleft, thereby reducing the enhancement of dopamine function in the brain, thereby reducing the symptoms of schizophrenia.
  • the dopamine transporter agonists of the invention may also be used in the form of a salt derived from a pharmaceutically or physiologically acceptable acid or base.
  • these salts include (1 ⁇ 4 is not limited to) salts with the following inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and salts with organic acids, while organic acids refer to acetic acid, oxalic acid, succinic acid, tartaric acid, Sulfonic acid and maleic acid.
  • the salt thereof includes a salt formed with an alkali metal or an alkaline earth metal such as sodium, potassium, calcium or magnesium, in the form of an ester, a carbamate or other conventional "prodrug" (when administered in this form) At the time, it can be converted into an active part in the body).
  • an alkali metal or an alkaline earth metal such as sodium, potassium, calcium or magnesium
  • the amount of the drug depends on the nature and extent of the disease and the condition in which the patient has received treatment.
  • the dosage is usually determined by the prescribing physician.
  • the clinical dose is 0.5-300 mg of dopamine transporter agonist per kilogram of body weight per day.
  • the present invention also provides a composition comprising the dopamine transporter agonist, preferably, the composition is a pharmaceutical composition. 01 ⁇ 9% ⁇ Preferably, a suitable amount of the dopamine transporter agonist of the total weight of the pharmaceutical composition of 0. 01-99%, preferably 0. 1-90%.
  • the composition may also contain a pharmaceutically acceptable carrier including, but not limited to, fillers, disintegrants, lubricants, glidants, effervescent agents, Flavoring agents, coating materials, dietary products, or slow/controlled release agents.
  • a pharmaceutically acceptable carrier including, but not limited to, fillers, disintegrants, lubricants, glidants, effervescent agents, Flavoring agents, coating materials, dietary products, or slow/controlled release agents.
  • the composition may be prepared in the form of a solid or gel, such as a pill, a tablet, a capsule or the like, depending on the mode of administration; or in a liquid form such as an injection or suspension. They are suitable for oral administration, rectal administration, topical administration or parenteral administration, or intravenous administration.
  • a "pharmaceutically acceptable” ingredient is a substance which is suitable for use in humans and/or animals without excessive adverse side effects (e.g., toxicity, irritability, and allergy), i.e., has a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically or food acceptable solvent, suspending agent or excipient for delivering the dopamine transporter agonist to an animal or human.
  • the carrier can be a liquid or a solid.
  • the solid composition for oral administration of the present invention can be used in the form of tablets, pills, capsules, powders, granules, drops, and the like. These solid compositions are mixed with one or more active substances and at least one inert diluent, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, and polyethylene. Pyrrolidone, Qiongyi, table glue, magnesium aluminosilicate, magnesium aluminate.
  • the composition may further contain an additive other than an inert diluent according to a usual method, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or Tianyi.
  • a co-solvent such as a cis. If it is a tablet or a preparation, it may be coated with a sugar coating such as sucrose, gelatin, hydroxymethylcellulose, hydroxypropylmethylcellulose or phthalate or a gastric-soluble or enteric film as needed. .
  • the liquid composition for oral administration includes a pharmaceutically acceptable emulsion, a solution, a suspending agent, a syrup, an elixir, etc., and the commonly used inert diluent includes purified water, and drunk.
  • the composition may contain, in addition to the inert diluent, an auxiliary agent such as a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, and a preservative.
  • auxiliary agent such as a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, and a preservative.
  • ''Injectables for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and opacifiers.
  • the aqueous solution and the suspension include distilled water for injection and physiological saline.
  • the water-insoluble solution and suspending agent include diethylene glycol, polyethylene glycol, cocoa butter, olive oil, castor oil and the like, alcohol such as ethanol, gum arabic, Tween 80 and the like. These compositions may also contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers (for example, lactose), and solubilizing agents (for example, Glutamate, aspartic acid). Sterile purposes can be achieved by sterilizing the above composition by filtration and using a sterilizing agent. Then, a sterile solid composition is prepared by using the above composition, and it can be utilized by dissolving it in a solvent with water or sterilizing before use.
  • composition of the dopamine transporter agonist or dopamine transporter agonist of the present invention can also be used in combination with other drugs for treating psychotic diseases and neurological diseases, depending on various needs. Further, the dopamine transporter agonist of the present invention can also be used in combination with an analgesic or analgesic drug having an addiction, thereby achieving an analgesic effect while preventing animal addiction.
  • the invention also encompasses a method of treating a dopaminergic hyperreactive disorder, the method comprising: administering to a subject in need thereof an effective amount of a dopamine transporter agonist.
  • the dopamine transporter agonist is a xanthone compound or a derivative thereof.
  • the present invention also encompasses a method of screening for a medicament for treating a mental disorder or a neurological disorder such as a dopaminergic hyperactive disorder.
  • the method comprises screening for a substance that promotes dopamine transporter transport or uptake of dopamine.
  • Such screening can be accomplished by establishing a cellular or animal model that can be used to observe the transport or uptake of dopamine transporters.
  • the dopamine transporter agonism theory was first proposed, and it was demonstrated that the dopamine transporter can be excited, and this agonistic effect can be used as a new target for treating hypertonic diseases of dopamine neurons.
  • the first screening of a class of dopamine transporter agonists provides a new drug for the clinical treatment of psychotic or neurological diseases, especially for the treatment of dopaminergic hyperactivity.
  • Luteolin, apigenin, soybean aglycone, quercetin and genistein were purchased from China National Drug Control Institute;
  • 1640 medium culture, calf serum was purchased from GIBC0 company;
  • 3 ⁇ 4-DA, 3 ⁇ 4-GABA, 3 ⁇ 4-Glutamic Acid was purchased from Amersham Pharmacia Biotech; morphine hydrochloride (batch number 20030124) was purchased from Shenyang No. 1 Pharmaceutical Factory; naloxone hydrochloride (lot number) 20040211) purchased from Beijing Sihuan Pharmaceutical Factory; Chinese hamster ovary cells (CH0) and COS-7 cells were purchased from ATCC, USA;
  • mice and SD rats were purchased from the Chinese Academy of Sciences Animal Center, Sprague-Dawley rats were purchased from Shanghai Slack Laboratory Animal Center; C57BL/6 mice were purchased from the Chinese Academy of Sciences Animal Center.
  • DAT dopamine transporter
  • GAT-1 y-aminobutyrate transporter
  • the cells After picking up the clone for one week, the cells were covered with the bottom of the well, and the medium was aspirated, and digested with trypsin. The cells in each well were seeded in respective wells of two 96-well plates. After the cells have filled the bottom of the well, one of the plates is used for isotope flow measurement. The cells in the well-transported wells of the corresponding plate were expanded stepwise, and the isotope flow rate was measured at each stage, and the cell line with the highest transport activity was selected.
  • D8 the cell clones with the highest transport activity were selected (named as D8, G1 cells) Seed preservation, establishment of a CH0 cell line that permanently expresses two neurotransmitters (DAT, GAT-1) of dopamine and Y-aminobutyric acid.
  • Results A cell line with high expression of DAT and GAT-1 transporter was obtained by measuring the isotope flow rate. A cell screening platform for DAT agonists was established.
  • COS-7 cell culture 1640 (GIBCO) medium, 10% FBS (PAA), penicillin and streptomycin were 100 IU/nd, respectively, cultured at 37 °C. After the cells are full, 0.25% trypsin (Shanghai Shenggong Bioengineering Co., Ltd.) digests and inoculates 2, polyamine transporter agonist in vitro screening and selection specificity determination
  • D8 cells were cultured in a 48-well plate (Costar) to cover the plate (approximately 60,000 cells per well). Discard the liquid. Wash once with PBS, aspirate the PBS solution, add 90 ul of HBS dOraM Hepes, lOOmM NaCl, PH8. 0) per well, incubate at 25 °C for 10 minutes, and add lOul of HBS reaction solution to each well. The experimental group and the positive control were added with 80 ul of HBS, 10 ul of different concentrations of the drug, and lOul 3 ⁇ 4-DA (Amersham Pharmacia Biotech), 100 mM vitamin C and ⁇ pajilin.
  • the ethanol extract of Suzi (SZ, purchased from Xuhui Chinese Herbal Pieces Factory) was extracted and separated into four parts, namely petroleum ether '(S.Z1), chloroform (SZ2), ethyl acetate (SZ3) and n-nonanol (SZ4).
  • SZ3 had the strongest dopamine uptake at 10 ⁇ g/ml, which was 8 times higher than that of the control group, as shown in Figure 1.
  • ' ' SZ3 was separated by polyacrylamide gel and divided into multiple parts (SZ2, SZ3, SZ4, SZ5, SZ6, SZ8, SZ9).
  • Activity tracking showed that at the concentration of 10 ⁇ g/ml, SZ9 The most vigorous, about 8 times the control group, see Figure 2.
  • the concentration of DAT uptake by the drug was increased to 150% of the negative control group (D8 cells without drug), that is, the concentration at which DAT activity increased by 50% was called EC 5 o, to evaluate the biological activity of the DAT agonist.
  • the EC50 activity of SZ92 reached 1.36.25 ⁇ , as shown in Figure 6. 2. Study on the specificity of dopamine transporter agonist selection
  • luteolin SZ92
  • acetylated SZ92 soy aglycone
  • quercetin quercetin
  • genistein genistein
  • apigenin apigenin at 10 g/ml
  • the inventors also examined the effects of different concentrations of each candidate drug on the glutamate transporter of COS-7 cells. It was found that luteolin (SZ92), soybean aglycone, quercetin, genistein, and apigenin had no agonistic effects on glutamate transporters of COS-7 cells at different concentrations, as shown in Figure 7. 8.
  • SZ3 had the strongest activity
  • An aqueous solution was prepared by dissolving 5000 lignin in lOQOrag water and dissolved by heating. The mixture is mixed, and the injection liquid which is packed into a concentration of 10 mg / 2 ml / is filled in a vial and sealed to be sterilized.
  • the luteolin tablet is prepared according to a method known to a person skilled in the art, wherein the tablet contains 5-10% luteolin (mass percentage) as needed, and the luteolin content can be increased or decreased. . Taking 100 g of luteolin, 560 g of microcrystalline cellulose, 380 g of anhydrous lactose, 200 g of magnesium stearate, 30 g of silica, tablets are prepared according to well-known tableting techniques and equipment, and stearic acid is removed from the above formula. Mix all ingredients except magnesium for 25-30 minutes, then sift the stearic acid 'magnesium and continue mixing. Then punched into pieces.
  • PC Phosphatidylcholine
  • Choi cholesterol
  • vitamin E1 ⁇ 2g vitamin E1 ⁇ 2g
  • luteolin 2mg dissolved in '20ml absolute ethanol, sonicated all luteolin, formulated into 1mg/ml drug weak.
  • saline group saline group
  • empty liposome group empty liposome group
  • luteolin (SZ92) liposome-embedded group Intraperitoneal injection of morphine hydrochloride, 6 times on the first day (8: 00, 9: 30 12: 00, 15: 00, 19: 00, 22: 00), the morphine dose was 2, 4, ' 6, 8, 8, 8 mg ' kg- 1 , 2 times the next day (8:00, 11: 00), morphine dose 8mg ⁇ kg" 1 , intraperitoneal injection (ip) naloxone hydrochloride (4mg ⁇ kg" 1 after the last injection of morphine hydrochloride for 3h ), observe all withdrawal symptoms within 30rain and score.
  • ip intraperitoneal injection
  • the empty liposomes and luteolin (SZ92) liposomes were intraperitoneally injected at a time of half an hour before morphine injection, at the same dose as each morphine injection. Rats with naloxone urged withdrawal to change the various withdrawal symptoms The score of the Yanagida Keji score (Table 2) was scored.
  • a 32cmX 16 C mX 30cm rectangular box with an open top is made of colored plexiglass plates, and the middle is partitioned into two equal parts by a baffle, and a 10 cm ⁇ 10 cm square channel is provided in the middle of the baffle plate. Animals pass freely. The sides of the box are painted white and black, and covered with clear glass. Place the shuttle box in a large isolation box with a 5W incandescent lamp and an image surveillance system on top.
  • Preconditioning stage experimental animals Bl/c57 mice, male, 20-25 g, 8 weeks old, 70 rats. The first half of the day. Shuttle in the box for 10 minutes, the second half for 20 minutes, the third half for 20 minutes, and check the preferred side stay time, screening 50 mice with similar preference scores for modeling. ⁇ , .
  • Modeling stage The mice were randomly divided into normal group, model group and SZ92 treatment group (dose were
  • the model group had a preference time of 654. 9 seconds in the white side box, and the normal control group had a preference time of 469 seconds in the white side box, which was significantly lower than the model group (0.001), cocaine dependence model. success.
  • the preference time of liposome-embedded SZ92 treatment group (1.7 mg/Kg, 3. 3 mg/Kgs 6. 7 mg/Kg) was 535.1 seconds, 516. 9 3 ⁇ 4 616. 3 seconds, respectively, which were significantly lower than the model. Group (0. 05 and / 0. 001) ( Figure 11).
  • Subcutaneous injection of luteolin (SZ92) liposome (5mg SZ92 / kg body weight / day) or the same volume ' 30 minutes after the solvent (liposome), morphine (5 mg / kg body weight / day) was injected subcutaneously.
  • the control group was injected subcutaneously with the same volume of liposomes and physiological salts.
  • Twenty minutes after morphine injection the animals were placed on a 55-inch hot plate.
  • the time range of the hind paws was 10-30 s, and the test was repeated at intervals of 15 min. The average of the two test results was the final result.
  • the standard of the test is the time of the animal's hind paw (latency of pain).
  • RESULTS The pain sensation period (the hindlimb time) of each group was: saline group 13. 381 seconds, empty liposome group
  • Example 7 Luteolin treatment of mouse schizophrenia model 'Experimental animals and groupings: References (An animal model of schizophrenia established by Wu Jinhua et al. using different experimental mouse strains. Acta Physiologica Sinica, 2003, 55: 381-387 ). Inbred C57BL/6 small, rat, male, body weight (20 ⁇ 2 g). It is divided into normal group, model group and treatment group.
  • the treatment group (SZ) was intraperitoneally injected with liposomes embedded in SZ92.
  • the normal group and the model group were replaced with the same volume of liposomes, and the mice were placed in a 48 0mX 24 cmX 20 cm rectangular experiment box with an open top. The box is covered with glass and pre-adapted for 30 minutes. '
  • the model group and the different concentration treatment groups were respectively treated with 0.6 mg/kg dizocilpine maleate (referred to as MK801,

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Abstract

L'invention se rapporte à l'utilisation de flavonoïdes ou de leurs dérivés pour produire des médicaments destinés à traiter des troubles psychiatriques et neurologiques, et à une composition contenant lesdits composés. Il a été suggéré puis prouvé qu'il est possible d'agiter le transporteur de la dopamine. L'invention concerne également un type d'agoniste du transporteur de la dopamine permettant de traiter des troubles psychiatriques et neurologiques, en particulier des troubles liés à une hyperactivité des nerfs dopaminergiques.
PCT/CN2007/001839 2006-06-23 2007-06-11 Agoniste du transporteur de la dopamine et ses utilisations WO2008000142A1 (fr)

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