WO2013091334A1 - Utilisation de rapamycine dans la préparation de médicaments pour le traitement de la schizophrénie - Google Patents

Utilisation de rapamycine dans la préparation de médicaments pour le traitement de la schizophrénie Download PDF

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Publication number
WO2013091334A1
WO2013091334A1 PCT/CN2012/074508 CN2012074508W WO2013091334A1 WO 2013091334 A1 WO2013091334 A1 WO 2013091334A1 CN 2012074508 W CN2012074508 W CN 2012074508W WO 2013091334 A1 WO2013091334 A1 WO 2013091334A1
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WIPO (PCT)
Prior art keywords
rapamycin
schizophrenia
mice
effect
spontaneous activity
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PCT/CN2012/074508
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English (en)
Chinese (zh)
Inventor
李艳琴
丁虹
林觉
郑春明
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武汉大学
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Publication of WO2013091334A1 publication Critical patent/WO2013091334A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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

Definitions

  • the present invention relates to the use of rapamycin for the preparation of a medicament for the treatment of schizophrenia, and belongs to the field of medical technology.
  • Schizophrenia is a serious mental disorder in mental illness with a prevalence of about 1%. Symptoms are divided into positive symptoms such as psychomotor excitability, hallucinations, delusions, etc. Negative symptoms such as lack of spontaneous, apathy, flexion disorders, etc., usually accompanied by cognitive disorders, the main pathological mechanism and central dopamine (D2 Hyperfunction is associated with poor prefrontal function.
  • the main anti-schizophrenia drugs include: The first generation includes traditional antipsychotics represented by chlorpromazine and haloperidol; the second generation includes risperidone, olanzapine, quetiapine, and aripipramine. Atypical antipsychotics represented by azole, ziprasidone and amisulpride.
  • DA dopamine
  • 5-HT serotonin
  • Drugs block the dopamine D2 receptors in the midbrain-cerebral cortex and midbrain-marginal system, but they also cause extrapyramidal effects because they also affect the DA function of the substantia nigra-striatum and nodule-funnel system. Reaction (EPS), as well as endocrine, metabolic changes and other adverse reactions.
  • EPS Reaction
  • the drug acts on other nerve conduction systems, such as blocking the alpha receptor of the adrenergic system, the M1 receptor of the choline system, and the HI receptor of the histamine system, such as cardiovascular, autonomic nervous system , as well as adverse reactions such as calming, lethargy, weight gain, and obesity.
  • the second-generation anti-schizophrenia drugs In addition to acting on the DA system, the second-generation anti-schizophrenia drugs also act on the 5-HT system, which has less effect on other nerve conduction systems and can reduce adverse reactions. It is effective for negative symptoms.
  • these current antipsychotics are for people with schizophrenia The treatment is only symptomatic, and far from treatment. Therefore, when patients with schizophrenia are relieved by treatment, they must continue the long-term maintenance treatment of the drug for several years or even life to prevent recurrence. Therefore, the current treatment of schizophrenia still lacks a thorough therapeutically effective drug.
  • Psychiatry, 2011, 198, 173 - 175 that genetic factors and some early environmental factors interfere with the normal development of the nervous system, leading to cell structural disorders during brain development, and no psychiatric symptoms in childhood, as they enter puberty or In early adulthood, under the circumstance of external environmental factors, the psychological integration function is abnormal and schizophrenia symptoms appear. Therefore, inhibiting abnormal neuronal plasticity during neurodevelopment is the key to schizophrenia treatment. There are no related therapeutic drugs.
  • the mammalian ram target (Ramamycin mTOR) is a serine/threonine kinase. Protein synthesis controlled by the mTOR signaling pathway is involved in neural plasticity formation (Dash PK, et al. J Neurosci, 2006, 26 (31): 8048-56. Parsons RG, et al. J
  • Rapamycin is a natural inhibitor of mTOR (Gingras AC, et al. Curr Top Microbiol
  • the present invention provides the use of rapamycin for the preparation of a medicament for treating schizophrenia, and the anti-schizophrenia medicament prepared by using the above product has good curative effect.
  • the technical solution provided by the invention is: The application of rapamycin in the preparation of a medicament for treating schizophrenia.
  • experimental mice were administered rapamycin 1, 2. 5, 5 mg/kg by intraperitoneal injection, and a mouse model of schizophrenia was prepared by using the electric shock stimulation method and MK-801 excitation.
  • rapamycin 1, 2, 5, 5 mg / kg One hour after the intraperitoneal injection of rapamycin 1, 2, 5, 5 mg / kg, the effects of rapamycin on the irritation and spontaneous activity of mice were observed by electric shock and intraperitoneal injection of MK-801.
  • the untreated mice were still irritated with an electric shock, and the behavioral score was 100%.
  • rapamycin After the administration of rapamycin, the effect of suppressing the irritation reaction was dose-dependent, that is, the low dose was ineffective, and the medium and high doses were Significant inhibition effect. Moreover, pre-administration of rapamycin treatment can prevent high-risk spontaneous activity caused by MK-801. It indicates that rapamycin can improve the symptoms of schizophrenia.
  • the rapamycin (English name Rapamycin, Sirolimus, RAPA; Chinese also known as: sirolimus) according to the present invention is a macrolide antibiotic, and the molecular formula of rapamycin is C51H79N013, and the molecular weight is 914. .17 is a white solid crystal, melting point 183 ⁇ 185 ° C lipophilic, soluble in organic solvents such as methanol, ethanol, acetone and chloroform, very slightly soluble in water, almost insoluble in ether.
  • the molecular structure of rapamycin is:
  • the present invention also provides a medicament for treating schizophrenia, which comprises an effective amount of rapamycin and an auxiliary material, which can be synthesized according to the conventional techniques commonly used in the pharmaceutical industry.
  • the present invention has the beneficial effects of:
  • the rapamycin of the present invention has a good effect, and the prepared drug is expected to fundamentally treat schizophrenia and prevent recurrence after stopping the drug.
  • Figure 1 shows the effect of rapamycin on spontaneous activity in normal mice.
  • Figure 2 is the effect of rapamycin on the spontaneous activity of MK-801 mice, * compared with the normal control group (P ⁇ 0.05); Rapamyciri. detailed description
  • Example 1 Effect of rapamycin on irritation response induced by plantar electroporation in mice
  • Rapamycin is a novel immunosuppressive agent with good curative effect, low toxicity and no nephrotoxicity.
  • rapamycin was selected as a drug against schizophrenia, and a small electric shock schizophrenia was established.
  • Drugs and reagents rapamycin are commercially available analytical reagents.
  • the mouse vocabulary was purchased from the Experimental Animal Center of Wuhan University.
  • mice were randomly divided into 4 dose groups of rapamycin 0, 1, 2.5 and 5 mg/kg. The administration was performed by intraperitoneal injection, and the behavioral index was detected 1 hour after the administration.
  • mice were screened before the experiment. A pair of mice were placed in an electric stimulation device, the lid was closed, the power was turned on, and the AC output knob was adjusted from 0 mV to 100 mV until the mice were An irritating response occurs, and the recorded voltage value is the voltage threshold at which the mouse is irritated. If the stimulus does not appear above lmin, it will be discarded. Then, each group of mice was administered with a corresponding dose of rapamycin for 1 hour, and again, whether or not an irritation reaction occurred.
  • mice were screened before the experiment. A pair of mice were placed in an electric stimulation device, the lid was closed, the power was turned on, and the AC output knob was adjusted from OmV to 100 mV until the mice were irritated. The recorded voltage value is the voltage threshold at which the mouse is irritated. If you have not stimulated for more than 1min, it will be discarded. Then, each group of mice was given 1 hour after the corresponding dose of rapamycin, and the irritation reaction was detected again at the threshold voltage of the foot shock. The behavioral score, ie the number of mice with irritable reaction after administration, was obtained. The ratio of the number of mice in which the irritating response occurred before administration. Experimental result 1. The effect of rapamycin on irritation response in mice
  • the untreated mice showed an irritation reaction before and after the electric shock of the foot, and the behavioral score was
  • Example 2 Effect of rapamycin on MK-801-induced high-risk spontaneous activity in mouse schizophrenia. This example selects rapamycin as a drug for high-risk activity against schizophrenia, and builds MK-801 schizophrenia. In a mouse model, we investigated the effect of rapamycin on the high-risk spontaneous activity in mice, and aimed to select a drug with high efficacy and low toxicity for high-risk spontaneous activity against schizophrenia. Materials and Methods
  • Rapamycin sigma-R0395; MK-801: sigma-M107; DMS0 and other reagents are commercially available analytical reagents.
  • the mouse vocabulary was purchased from the Experimental Animal Center of Wuhan University.
  • mice were randomly divided into normal control + rapamycin 0, 1, 2.5, and 5 mg/kg groups and MK-801 model + rapamycin 0, 1, 2.5, and 5 mg/kg groups. . Dosing is administered intraperitoneally. Behavioral indicators were tested 1 hour after dosing.
  • mice Each group of mice was given the corresponding dose of rapamycin for 1 hour, MK-801 model group was given 0.5 mg/kg of MK-801, the normal control group was given the corresponding vehicle, and the spontaneous control was detected after the administration. Activity for 1 hour.
  • mice Each group of mice was given a corresponding dose of rapamycin in the spontaneous activity test box to record the number of shuttle lattices. One hour later, the vehicle was injected intraperitoneally with MK-801 and spontaneous activity was recorded for 1 hour.
  • the spontaneous activity of the mouse uses the DigBehv spontaneous activity video analysis system (manufactured by Shanghai Jiliang Software Technology Co., Ltd.), which is composed of 4 spontaneous activity observation boxes and video synthesizers with a size of 25 cmX 25 cmX 40 cm (length X width X height). , video pattern sampling card and analysis software.
  • the system can track video of mouse activities, automatically record mouse activity trajectories, and calculate activity paths.
  • the indicators for spontaneous activity evaluation are: The total distance of activity of the mouse within a certain period of time (such as 60 min), that is, the total distance becomes longer and the spontaneous activity increases.
  • mice Each group of mice was given the corresponding dose of rapamycin in the spontaneous activity test box to record the number of shuttle lattices.
  • the spontaneous activity of the mouse adopts the DigBehv spontaneous activity video analysis system (manufactured by Shanghai Jiliang Software Technology Co., Ltd.), which is a spontaneous activity observation box and video synthesizer with 4 specifications of 25 cmX 25 cmX 40 cm (length X width X height). , video pattern sampling card and analysis software.
  • the system can video track mouse activities, automatically record mouse activity trajectories, and calculate activity paths.
  • the indicators for spontaneous activity evaluation are: The total distance of activity of the mouse within a certain period of time (such as 60 min), that is, the total distance becomes longer and the spontaneous activity increases.
  • rapamycin After administration of rapamycin in the MK-801 model group, it has a significant inhibitory effect on the spontaneous activity from MK-801 to the hair, that is, it is ineffective at low doses of 1 mg/g, medium and high doses (2.5 mg/g, 5. Omg/g) showed a significant inhibitory effect, and the results are shown in Figure 2. The difference was significant.
  • rapamycin can improve schizophrenia Highly spontaneous spontaneous activity response.
  • Rapamycin can effectively improve the symptoms of schizophrenia induced by plantar electric shock in mice, and its effect is dose-dependent and has remarkable curative effect.

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

Abstract

La présente invention concerne l'utilisation de rapamycine dans la préparation de médicaments pour traiter la schizophrénie. La rapamycine dans la présente invention fournit un médicament efficace pour traiter les symptômes d'irritabilité et d'activité intense de la schizophrénie.
PCT/CN2012/074508 2011-12-22 2012-04-23 Utilisation de rapamycine dans la préparation de médicaments pour le traitement de la schizophrénie WO2013091334A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2011104350585A CN102488687A (zh) 2011-12-22 2011-12-22 雷帕霉素在制备治疗精神分裂症中的应用
CN201110435058.5 2011-12-22

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JP2014520811A (ja) 2011-06-29 2014-08-25 ザ トラスティース オブ コロンビア ユニバーシティ イン ザ シティ オブ ニューヨーク 統合失調症の易罹病性及び認知機能障害と関連付けられるニューロン結合の阻害剤
WO2014145857A1 (fr) * 2013-03-15 2014-09-18 The Trustees Of Columbia University In The City Of New York Ciblage thérapeutique de la voie mtor dans des affections neurologiques
CN112877419A (zh) * 2021-01-20 2021-06-01 武汉大学 预测精神分裂症发生风险的dna甲基化标记物及筛选方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187127A (zh) * 1995-06-07 1998-07-08 吉尔福特药品有限公司 旋转异构酶活性抑制剂
WO2010083044A1 (fr) * 2009-01-16 2010-07-22 Massachusetts Institute Of Technology Diagnostic et traitement de troubles du spectre autistique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1187127A (zh) * 1995-06-07 1998-07-08 吉尔福特药品有限公司 旋转异构酶活性抑制剂
WO2010083044A1 (fr) * 2009-01-16 2010-07-22 Massachusetts Institute Of Technology Diagnostic et traitement de troubles du spectre autistique

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