WO2011083823A1 - Agent prophylactique ou thérapeutique pour la schizophrénie - Google Patents

Agent prophylactique ou thérapeutique pour la schizophrénie Download PDF

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WO2011083823A1
WO2011083823A1 PCT/JP2011/050124 JP2011050124W WO2011083823A1 WO 2011083823 A1 WO2011083823 A1 WO 2011083823A1 JP 2011050124 W JP2011050124 W JP 2011050124W WO 2011083823 A1 WO2011083823 A1 WO 2011083823A1
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receptor
dopamine
schizophrenia
methyl ether
serotonin
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PCT/JP2011/050124
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English (en)
Japanese (ja)
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正彌 遠山
昌一 島田
泰一 片山
伸介 松崎
徹 平塚
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国立大学法人大阪大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • A61K31/4375—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 nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a preventive or therapeutic agent for schizophrenia.
  • Schizophrenia is a mental disorder that shows various symptoms such as hallucinations and delusions. Symptoms of schizophrenia are mainly positive symptoms in the acute phase (such as hallucinations, delusions, disruption of thoughts), and negative symptoms that become conspicuous in the chronic phase (emotion dullness, motivation or lack of voluntaryness, social Withdrawal). Schizophrenia is a disease with a high incidence of about 1%, but the cause is still unknown.
  • D2 receptors dopamine receptors
  • serotonin receptors 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors
  • D2 receptors dopamine receptors
  • 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors receptors that are closely related to psychiatric symptoms such as schizophrenia. It has been.
  • the pharmacological effects of conventional typical antipsychotic drugs on hallucinations and delusions were based on the action control of dopamine D2 receptor.
  • typical antipsychotics were effective for the positive symptoms of schizophrenia but had little effect on the negative symptoms.
  • typical antipsychotics have the problem of strong side effects because they have an action of suppressing dopamine nerves.
  • atypical antipsychotics which are said to be effective for negative symptoms of schizophrenia, have been developed and have been used in place of typical antipsychotics.
  • This atypical antipsychotic acts on the dopamine receptor and serotonin (5HT) receptor, and since the action control of the dopamine receptor is not as strong as that of the typical antipsychotic, compared with the typical antipsychotic.
  • 5HT dopamine receptor and serotonin
  • Non-Patent Document 1 states that geisocidin methyl ether does not act on dopamine receptors.
  • all antipsychotic drugs typically antipsychotic drugs and atypical antipsychotic drugs
  • D2 receptor Non-patent Document 2
  • An object of the present invention is to provide a medicament that has few side effects and is effective in the prevention or treatment of schizophrenia.
  • Yokukansan which is a Chinese medicine (Chinese medicine), improves the abnormal behavior of schizophrenia model mice and suppresses prepulse ( It was found that the improvement effect of prepulse (inhibition) was shown, and from this, it was found that Yokukansan is effective for the prevention or treatment of positive symptoms of schizophrenia.
  • Yokukansan is a highly safe Kampo medicine that has been proven to have few side effects in conventional clinical use.
  • D2 receptors dopamine receptors
  • serotonin receptors 5-HT1A, 5-HT2A, 5-HT2C receptors, and 5-HT7 receptors
  • GM geissoschizine methylether
  • GM acted as a partial agonist (partial agonist) on the dopamine D2 receptor.
  • GM acted as an agonist (agonist) or antagonist (antagonist) at the serotonin receptor.
  • GM acts as an agonist and its IC 50 value was 5.01 ⁇ M.
  • GM mainly acted as an antagonist, and its IC 50 value was 31.6 ⁇ M.
  • the activity as a partial agonist was slight for this receptor.
  • GM acted as an antagonist and its IC 50 value was 50.1 ⁇ M.
  • GM further acted as an antagonist to the 5-HT7 receptor, with an IC 50 value of 610 nM.
  • GM's characteristics of agonistic and antagonistic activity on 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors are similar to those of atypical antipsychotics on serotonin receptors Many points were recognized, and it was found that GM exerts an anxiolytic action, an antipsychotic action and the like through this action. Further, since GM is a component contained in herbal medicines, it has been found that even if administered for a long period of time, it has little side effects and can be a highly safe therapeutic drug for schizophrenia. Furthermore, by modifying GM based on such knowledge about the action of GM, it becomes possible to develop a new therapeutic or preventive drug for schizophrenia. The present inventors have further studied based on these findings, and have completed the present invention. That is, the present invention relates to a preventive or therapeutic agent for schizophrenia and the like, and includes the following inventions.
  • a prophylactic or therapeutic agent for schizophrenia characterized by containing giesocidin methyl ether as an active ingredient.
  • a partial agonist of a dopamine receptor characterized in that it contains gatesocidin methyl ether as an active ingredient.
  • the partial agonist according to (2), wherein the dopamine receptor is a dopamine D2 receptor.
  • a medicament for partially activating a dopamine receptor and activating a serotonin receptor characterized in that it contains gatesocidin methyl ether as an active ingredient.
  • a medicament for partially actuating a dopamine receptor and inhibiting a serotonin receptor characterized in that it contains gatesocidin methyl ether as an active ingredient.
  • the dopamine receptor is a dopamine D2 receptor
  • the serotonin receptor is at least one receptor selected from the group consisting of a 5-HT2A receptor, a 5-HT2C receptor, and a 5-HT7 receptor.
  • the present invention also includes the following methods.
  • (10) A method for preventing or treating schizophrenia, which comprises the step of administering giesocidin methyl ether to a mammal.
  • (11) A method for partially activating a dopamine receptor comprising the step of administering gesocidin methyl ether to a mammal.
  • (12) A method of partially activating a dopamine receptor and activating a serotonin receptor, comprising a step of administering gesocidin methyl ether to a mammal.
  • (13) A method for partially activating a dopamine receptor and inhibiting a serotonin receptor, comprising the step of administering gesocidin methyl ether to a mammal.
  • (14) A method for preventing or treating schizophrenia, comprising a step of administering Yokukansan to a mammal.
  • giesocidin methyl ether for producing a prophylactic or therapeutic agent for schizophrenia.
  • gassocidin methyl ether for producing a partial agonist of a dopamine receptor.
  • giesocidin methyl ether for producing a medicament for partially activating dopamine receptors and activating serotonin receptors.
  • gatesocidin methyl ether for the manufacture of a medicament for partially activating dopamine receptors and inhibiting serotonin receptors.
  • yokukansan to produce a preventive or therapeutic agent for schizophrenia.
  • Gaysocidin methyl ether for use in the prevention or treatment of schizophrenia.
  • Gaysocidin methyl ether as a partial agonist of dopamine receptors.
  • Gaysocidin methyl ether as a medicament for partially activating dopamine receptors and activating serotonin receptors.
  • Gaysocidin methyl ether as a medicament for partially activating dopamine receptors and inhibiting serotonin receptors.
  • Yokukansan for use in the prevention or treatment of schizophrenia.
  • the preventive or therapeutic agent of the present invention acts as a partial agonist (partial agonist) of dopamine receptor and acts as an agonist or antagonist of serotonin receptor, schizophrenia can be prevented or treated. And there are few side effects.
  • FIG. 1 is a diagram showing the results (drug response curve) of the effects of components contained in Yokukansan on the mouse 5-HT1A receptor.
  • FIG. 2 is a graph of 5-gammasocidin methyl ether (denoted as GM in FIG. 2), Rhynchophylline (denoted as Rhy in FIG. 2), and Hirsutine (denoted as Hir in FIG. 2). It is a figure which shows the result of having investigated the inhibitory effect with respect to HT2A receptor.
  • FIG. 3 is a graph showing the results of examining the inhibitory action of geisocidin methyl ether on the 5-HT2A receptor.
  • FIG. 4 is a graph showing the results of examining the inhibitory action of geisocidin methyl ether on the 5-HT2C receptor.
  • FIG. 5 is a diagram showing the results of examining the action of gassocidin methyl ether as a partial agonist on the dopamine D2 receptor.
  • FIG. 6 is a graph showing the results of examining the inhibitory action of geisocidin methyl ether on the 5-HT7 receptor.
  • prevention refers to delaying or preventing the onset of a symptom or disease and its associated symptoms, preventing the subject from acquiring a symptom or disease, or the subject to a symptom or disease. Means reducing the risk of earning.
  • Treatment refers to the complete cure of a symptom or disease, the suppression of the progression and / or worsening of the symptom without complete cure, and the progression of the symptom or disease, or the It means to improve part or all and lead to the direction of healing.
  • the preventive or therapeutic agent for schizophrenia of the present invention contains gaysocidin methyl ether (GM) as an active ingredient.
  • GM gaysocidin methyl ether
  • GM is an alkaloid contained in chowaku, etc., which is a herbal medicine of Chinese medicine such as Yokukansan.
  • the GM used in the present invention may be synthesized or derived from a plant.
  • GM can be obtained, for example, according to the method described in Aimi et al., 1977, Chem. Pharm. Bull. 25 (8), 2067-2071 or Mimaki et al., Yakugaku Zasshi 117 (12), (1011-1021. It can also be extracted and isolated from U. sinensis (Oliv. Havil). In the present invention, such commercially available products or GM extracted and isolated from U. sinensis (Oliv.) Havil can be used.
  • a crude drug containing GM can also be used.
  • Chotoro etc. is preferable. Choito is sold as a crude drug powder, an extract powder (dried extract), and the like.
  • Azusa Choto is contained as an extract powder (dried extract) in traditional Chinese medicines (Chinese medicines) such as Yokukansan.
  • a commercially available herbal powder or extract powder from Chotoen, or a Chinese herbal medicine (Chinese medicine) such as Yokukansan containing Chotoen can be used.
  • a Chinese medicine provided by combining a crude drug with a crude drug such as a fish rattan containing GM.
  • traditional Chinese medicines including Chotan-san include Yokukansan, Tokiyaku Yakuyaku Hakuo-Kyoto, Yokukan-Sanyaku Hakuren, Yokukan-Sanka-Hakka.
  • a prophylactic or therapeutic agent for schizophrenia containing a Chinese medicine containing such a fish rattan is one of the preferred embodiments of the present invention.
  • Yokukansan is preferable.
  • Use of Yokukansan as a preventive or therapeutic agent of the present invention is one of the more preferred embodiments of the present invention.
  • a preventive or therapeutic agent for schizophrenia containing yokukansan is also one aspect of the present invention.
  • Yokukansan commercially available Kampo medicines can be used.
  • Commercially available Chinese herbal medicines include, for example, Tsumura Yokukansan Extract Granules (trade name) (trade name, manufactured by Tsumura Co., Ltd., Japan) and Osugi Yokukansan (trade name) (produced by Tokiwa Pharmaceutical Co., Ltd., Japan).
  • Yonkansan trade name, manufactured by Kyokugen Pharmaceutical Co., Ltd., Japan
  • Tsumura Yokukansan Extract Granules (trade name) (manufactured by Tsumura Corporation, Japan), which is a medical herbal medicine, is preferred.
  • the preventive or therapeutic agent of the present invention may or may not contain components other than Chinese medicine such as GM, herbal medicine containing GM, or Yokukansan including Chotan.
  • Chinese medicine such as GM, herbal medicine containing GM, or Yokukansan including Chotan.
  • components other than GM herbal medicines containing GM, and traditional Chinese medicines such as yokukansan, pharmaceutically acceptable carriers and the like can be used.
  • GM a herbal medicine containing GM
  • a traditional Chinese medicine such as Yokukansan
  • the prophylactic or therapeutic agent of the present invention is prepared by mixing GM, a herbal medicine containing GM or a Chinese medicine such as Yokukansan and a pharmaceutically acceptable carrier to be blended as desired by a known method. Can be easily prepared.
  • Examples of the dosage form of the preventive or therapeutic agent of the present invention include oral preparations such as solid preparations such as tablets, powders, granules and capsules; liquid preparations such as emulsions, syrups and suspensions. .
  • Examples of preparations for parenteral administration include injections and drops.
  • the dosage form of the preventive or therapeutic agent of the present invention is preferably an oral dosage form.
  • various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid formulations; solvents in liquid formulations, dissolution Adjuvants, suspending agents, isotonic agents, buffers, soothing agents and the like can be mentioned. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include, for example, sugars or sugar alcohols such as lactose, corn starch, maltose, mannitol; starches or starch derivatives such as corn starch, dextrin, pregelatinized starch; celluloses such as crystalline cellulose and hydroxypropyl cellulose And cellulose derivatives; light anhydrous silicic acid and the like.
  • sugars or sugar alcohols such as lactose, corn starch, maltose, mannitol
  • starches or starch derivatives such as corn starch, dextrin, pregelatinized starch
  • celluloses such as crystalline cellulose and hydroxypropyl cellulose And cellulose derivatives
  • light anhydrous silicic acid and the like Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.
  • the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate;
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
  • Preferable examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate and the like.
  • Preferable examples of the soothing agent include benzyl alcohol.
  • Preferable examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Preferable examples of the antioxidant include sulfite and ascorbic acid.
  • the GM content of the preventive or therapeutic agent of the present invention is not particularly limited.
  • the content of GM is preferably about 0.0005 to 0.05% by mass of the normal preparation, more preferably about 0.005 to 0.05% by mass.
  • the preventive or therapeutic agent of the present invention contains a crude drug containing GM or yokukansan, it is preferable that the content of GM falls within the above range.
  • the prophylactic or therapeutic agent of the present invention contains a herbal medicine containing GM, for example, a fish rattan
  • the content of the fish rattan is, for example, a solid preparation
  • the amount is about 0.003 to 0.1% by mass, preferably about 0.01 to 0.03% by mass.
  • the content of yokukansan in the preventive or therapeutic agent of the present invention is, for example, a solid preparation, About 10 to 95% by mass, preferably about 20 to 90% by mass, and more preferably about 20 to 80% by mass.
  • the administration method of the preventive or therapeutic agent of the present invention is preferably oral administration.
  • the dose and frequency of administration of the prophylactic or therapeutic agent of the present invention vary depending on age, body weight, dosage form, etc., but when the prophylactic or therapeutic agent of the present invention is orally administered, the daily dose per adult is 1 kg of body weight.
  • the GM is usually about 0.005 to 0.05 mg, preferably about 0.01 to 0.02 mg. This amount is usually preferably administered orally in 1 to 3 divided doses per day.
  • the dose is usually about 0.01-0.
  • the dose is 1 g, preferably about 0.03 to 0.08 g. This amount is usually preferably administered orally in 1 to 3 divided doses per day.
  • the above-mentioned TSUMURA Yokukansan extract granule (for medical use) (trade name, manufactured by Tsumura Corporation, Japan) is preferable.
  • the preventive or therapeutic agent of the present invention can be suitably used for the prevention or treatment of schizophrenia because GM acts as a partial agonist for dopamine receptors and also acts on setronin receptors. .
  • mammals such as humans, mice, rats, rabbits, dogs, cats, cows, monkeys, and pigs are preferable, and humans are more preferable.
  • a mammal that has developed or is likely to develop schizophrenia is preferable, and a mammal that has developed schizophrenia is more preferable.
  • the method for selecting a mammal that has developed schizophrenia to which the preventive or therapeutic agent of the present invention is administered is not particularly limited, and is a commonly used diagnostic method, for example, prepulse inhibition (PPI). Can be selected by testing.
  • PPI prepulse inhibition
  • the preventive or therapeutic agent of the present invention has few side effects, it can be suitably used for preventing schizophrenia.
  • the onset of schizophrenia can be delayed or prevented by administering the preventive or therapeutic agent of the present invention to a mammal that may develop schizophrenia.
  • GM contained in the preventive or therapeutic agent of the present invention acts as a partial agonist of dopamine receptors. Therefore, the preventive or therapeutic agent of the present invention can be used as a partial agonist of dopamine receptors.
  • a partial agonist of a dopamine receptor containing gassocidin methyl ether as an active ingredient is also one aspect of the present invention.
  • the partial agonist of the present invention and preferred embodiments thereof are the same as the above-mentioned preventive or therapeutic agent.
  • Examples of the dopamine receptor include dopamine D2 receptor.
  • the partial agonist of the present invention is suitable as a partial agonist of dopamine D2 receptor.
  • the partial agonist of the present invention acts as a partial agonist for the dopamine receptor.
  • GM acts on the serotonin receptor, it is used as a serotonin receptor agonist, partial agonist or antagonist. It is something that can be done.
  • serotonin receptors include 5-HT1A receptor, 5-HT2A receptor, 5-HT2C receptor, 5-HT7 receptor and the like.
  • GM acts as an agonist, for example, for the 5-HT1A receptor.
  • GM acts primarily as an antagonist for the 5-HT2A receptor, but acts as an antagonist for the 5-HT2C receptor.
  • GM acts as an antagonist for the 5-HT7 receptor.
  • the prophylactic or therapeutic agent of the present invention is suitably used as a medicament for partially activating dopamine receptors and activating serotonin receptors.
  • a medicament for partially activating a dopamine receptor containing gaysocidin methyl ether as an active ingredient and activating a serotonin receptor is also one aspect of the present invention.
  • the medicament of the present invention and preferred embodiments thereof are the same as the prophylactic or therapeutic agent described above.
  • the dopamine receptor is preferably a dopamine D2 receptor. Since GM acts as an agonist for the 5-HT1A receptor, the 5-HT1A receptor is preferred as the serotonin receptor.
  • the medicament of the present invention can be suitably used for partially activating dopamine D2 receptor and activating 5-HT1A receptor.
  • the prophylactic or therapeutic agent of the present invention is suitably used as a medicament for partially activating dopamine receptors and inhibiting serotonin receptors.
  • a medicament for partially activating a dopamine receptor containing gassocidin methyl ether as an active ingredient and inhibiting the serotonin receptor is also one aspect of the present invention.
  • the medicament of the present invention and preferred embodiments thereof are the same as the prophylactic or therapeutic agent described above.
  • the dopamine receptor is preferably a dopamine D2 receptor. Since GM acts as an antagonist to the 5-HT2A receptor, 5-HT2C receptor and 5-HT7 receptor, the serotonin receptor includes 5-HT2A receptor, 5-HT2C receptor and 5-HT2A receptor. One or more of the HT7 receptors are preferred.
  • the medicament of the present invention partially activates the dopamine D2 receptor and inhibits at least one receptor selected from the group consisting of 5-HT2A receptor, 5-HT2C receptor and 5-HT7 receptor. Can be suitably used.
  • a medicament for partially activating dopamine D2 receptor containing gassocidin methyl ether as an active ingredient and inhibiting 5-HT2A receptor and / or 5-HT2C receptor is also one aspect of the present invention.
  • a medicament for inhibiting the body is also one aspect of the present invention.
  • One preferred embodiment is a medicament for partially activating dopamine D2 receptor and inhibiting 5-HT2A receptor, 5-HT2C receptor and 5-HT7 receptor.
  • a medicament for partially activating dopamine D2 receptor containing gassocidin methyl ether as an active ingredient, activating 5-HT1A receptor, and inhibiting 5-HT2A receptor and / or 5-HT2C receptor This is one of the present inventions.
  • a medicament for inhibiting at least one receptor selected from the above is also one aspect of the present invention.
  • One preferred embodiment is a medicament for partially activating dopamine D2 receptor, activating 5-HT1A receptor and inhibiting 5-HT2A receptor, 5-HT2C receptor and 5-HT7 receptor. is there.
  • the medicament of the present invention and preferred embodiments thereof are the same as the prophylactic or therapeutic agent described above.
  • Gaysocidin methyl ether has the effect of partially activating dopamine D2 receptor, activating 5-HT1A receptor and inhibiting 5-HT2A receptor and 5-HT2C receptor as described above. Furthermore, gissocidin methyl ether has an action of inhibiting 5-HT7 receptor. For this reason, gaysocidin methyl ether, and herbal medicines containing it, such as herbal medicine and yokukansan, are not only schizophrenia, but also depression, depression, tension, anxiety, sleep disorders, psychosomatic disorders, autonomic dysfunction, It is useful for the prevention or treatment of neurosis, post-traumatic stress syndrome (PTSD), migraine and the like.
  • PTSD post-traumatic stress syndrome
  • the present invention also includes a method for preventing or treating schizophrenia, which comprises the step of administering gatesocidin methyl ether to a mammal.
  • the invention also encompasses a method of partially activating dopamine receptors comprising the step of administering gesocidin methyl ether to a mammal.
  • the present invention also encompasses a method of partially activating dopamine receptors and activating serotonin receptors comprising the step of administering gatesocidin methyl ether to a mammal.
  • the present invention also encompasses a method of partially activating dopamine receptors and inhibiting serotonin receptors comprising the step of administering gatesocidin methyl ether to a mammal.
  • preferred embodiments and the like when geisocidin methyl ether is administered to a mammal are the same as the above-described method for administering a prophylactic or therapeutic agent for schizophrenia.
  • Preferred embodiments of the dopamine receptor and serotonin receptor in the present invention are also the same as those in the above-mentioned preventive or therapeutic agent.
  • the present invention also includes gaysocidin methyl ether for use in the prevention or treatment of schizophrenia.
  • the present invention also includes gaysocidin methyl ether as a partial agonist of dopamine receptors.
  • the present invention also includes gaysocidin methyl ether as a medicament for partially activating dopamine receptors and activating serotonin receptors.
  • the present invention also includes gaysocidin methyl ether as a medicament for partially activating dopamine receptors and inhibiting serotonin receptors.
  • gaysocidin methyl ether is used as an active ingredient such as a preventive or therapeutic agent for schizophrenia, a partial agonist of dopamine receptor, and the like.
  • Preferred embodiments of the dopamine receptor and serotonin receptor in the present invention are also the same as those in the above-mentioned preventive or therapeutic agent.
  • the influence of components contained in Yokukansan on serotonin receptor or dopamine D2 receptor is caused by forcibly expressing various serotonin receptor or dopamine D2 receptor cDNA in HEK293 cells and using the cells. It investigated by examining the sensitivity of a drug by the calcium imaging method.
  • the 5-HT1A receptor is coupled to the Gi protein, which is one of the G proteins, and reduces cAMP. Therefore, the expression of the 5-HT1A receptor alone changes the intracellular calcium concentration by the calcium imaging method. It cannot be measured.
  • G.alpha proteins and chimeric constructs human full-length G.alpha 16, from HL60 cells, a human leukemia cell line, were obtained by reverse transcription PCR (RT-PCR) method.
  • G ⁇ 15 G ⁇ 16 mouse ortholog
  • RT-PCR reverse transcription PCR
  • G ⁇ 16 (GenBank Accession No. NM_002068) sense 5'-CGATGCCACCCGGTGCCGACTGA-3 '(224-246) (SEQ ID NO: 1) And antisense 5′-CCTGGGTCACAGCAGGTTGATCT-3 ′ (1367-1389) (SEQ ID NO: 2) was used.
  • Complementary DNA (cDNA) of mouse full-length G ⁇ 0 , G ⁇ i2 , and G ⁇ i3 was obtained using the following primers from mice containing the striatum and prefrontal cortex (C57BL / 6J: purchased from Charles River, Japan) Amplified in brain tissue.
  • G ⁇ 0 , G ⁇ i2 and G ⁇ i3 are all G proteins.
  • G ⁇ 0 GenBank Accession No. NM_010308
  • antisense 5′-AGAGGTCAGTACAAGCCGCA-3 ′ 1367-1389
  • G ⁇ i2 (GenBank Accession No. NM_008138) sense 5'-GAACTGCGGACCTGAGAGCT-3 '(9-28) (SEQ ID NO: 7) And antisense 5′-TCAGAAGAGGCCACAGTCCTTCA-3 ′ (1171-1193) (SEQ ID NO: 8) was used.
  • G ⁇ i3 (GenBank Accession No. NM_010306) sense 5'-ACCCGTCTCCGCCGGTGTGT-3 '(31-50) (SEQ ID NO: 9) And antisense 5′-CCTCTCAATAAAGCCCACATTCCT-3 ′ (1155-1178) (SEQ ID NO: 10) was used.
  • chimeras were constructed by PCR using human G ⁇ 16 as a template and appropriate G ⁇ complementary DNA (cDNA) from mouse.
  • the C-terminal 44 amino acids of human G ⁇ 16 were substituted with the C-terminal 44 amino acids of any of the proteins G ⁇ 0 , G ⁇ i2 and G ⁇ i3 to construct a chimera based on G ⁇ 16 (respectively, G ⁇ 16/0 , G ⁇ 16 / i2 and G ⁇ 16 / i3 ).
  • All full-length G ⁇ -subunit cDNAs were subcloned into pcDNA3.1 (+) mammalian expression vector (Invitrogen, Carlscad, Calif.).
  • HEK293T Human embryonic kidney 293T (HEK293T) cells were treated with Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% (v / v) fetal calf serum (FCS). The cells were cultured at 37 ° C. in a humidified condition containing 5% CO 2 . For transfection, cells were seeded on 100 mm dishes or uncoated coverslips in a 35 mm chamber. After culturing at 37 ° C.
  • DMEM Dulbecco's Modified Eagle Medium
  • FCS fetal calf serum
  • the cells were washed with DEME, and using LipofectAmine (registered trademark) 2000 reagent (manufactured by Invitrogen) according to the manufacturer's instructions, plasmid and receptor containing the cDNA of the G ⁇ subunit.
  • the cells were transfected with both plasmids containing cDNA.
  • the efficiency of transfection was assessed by co-transfection with a green fluorescent protein (GFP) receptor plasmid or by immunohistochemistry. As a result, typical transfection efficiency reached> 70%.
  • GFP green fluorescent protein
  • the transfected HEK293T cells on the cover glass were transferred to the assay chamber 24 hours later, and 5 ⁇ M Fura-2 / AM (Invitrogen) was loaded for 30 minutes at room temperature.
  • the cells were washed with 500 ⁇ L assay buffer (10 mM HEPES, 130 mM NaCl, 10 mM glucose, 5 mM KCl, 2 mM CaCl 2 and 1.2 mM MgCl 2 , pH 7.4) and then a peristaltic pump (Pharmacia) ) was used to stimulate the cells by perfusing the assay chamber with the test compound for 15 seconds at a flow rate of 5 mL / min.
  • assay buffer 10 mM HEPES, 130 mM NaCl, 10 mM glucose, 5 mM KCl, 2 mM CaCl 2 and 1.2 mM MgCl 2 , pH 7.4
  • a peristaltic pump Pharmacia
  • Cells loaded with Fura-2 were randomly selected (100 cells per assay), and the effects of test compounds on intracellular calcium mobilization were measured using the commercially available ARGUS / HisCa system (product name, Hamamatsu Photonics, Shizuoka, Japan) ).
  • the system was set in a bottom-read using two separate excitation wavelengths (340 nm and 380 nm) and an emission wavelength of 510 nm (detection wavelength).
  • the application of test compound to the cells was spaced 180-300 seconds apart so that the cells were not desensitized by the influence of the previously used ligand.
  • the ratio (510 nm fluorescence intensity at excitation 340 nm / 510 nm fluorescence intensity at excitation 380 nm) was determined by calculating the fluorescence intensity at 510 nm at excitation wavelengths of 340 nm and 380 nm with ARGUS / HisCa Version 1.65 software. For further analysis, cells that exhibited concentration-dependent intracellular calcium mobilization were selected after application of test compounds (10-15 cells per assay).
  • Example 1 The effect of yokukansan on the abnormal behavior of mice was examined by the following experiment.
  • the Yokukansan the Yokukansan extract preparation manufactured by Tsumura Corporation (Japan), trade name “Tsumura 54” was used.
  • the Yokukansan extract preparation, trade name “Tsumura No. 54” manufactured by Tsumura Corporation (Japan) used in the experiment is also simply referred to as “TJ-54”.
  • Polyinosine polycytidic acid (polyI: C) (20 mg / kg) was intraperitoneally administered to pregnant mice (C57BL / 6J: purchased from Charles River, Japan) at approximately 12.5 days of pregnancy. They were born (Makinodan M et al, J Brain Disease, 1: 1-6, 2009).
  • Yokukansan was effective in the positive and negative symptoms of schizophrenia relatively early after administration. From these results, it was considered that yokukansan may act simultaneously on multiple receptors such as dopamine receptor and serotonin receptor (5-HT receptor). In addition, it is known that a partial agonist (partial agonist) of dopamine D2 receptor functions as a dopamine-based stabilizer. For this reason, it was thought that yokukansan may act as a partial agonist or partial antagonist for the dopamine D2 receptor or 5-HT receptor.
  • Example 2 The influence of each component of Yokukansan on 5-HT receptors was examined.
  • the test compounds used are the following seven alkaloids contained in Akira Choto, one of the herbal medicines that make up Yokukansan. These alkaloids were all extracted and purified by Tsumura.
  • Alkaloid is a generic name for naturally occurring organic compounds that contain nitrogen atoms and show basicity. However, alkaloids often show strong physiological activity, and medicines used in Western medicine are also basically derived from alkaloids or alkaloids. Many are skeletons.
  • Corinoxeine Rhynchophylline Isorhynchophylline Isocorynoxeine Geissoschizine methylether (GM) Hirsuteine Hirsutine
  • test solutions were dissolved in polyoxyethylene sorbitan monooleate to prepare test solutions.
  • Each test solution contains any one of the above seven alkaloids.
  • a solution containing serotonin (5HT) (manufactured by Sigma) was used.
  • the concentration of each alkaloid or control serotonin in the test solution was 100 pM to 100 ⁇ M.
  • calcium imaging was performed according to the method described above, and the influence of the test compound on the 5-HT1A receptor was examined.
  • cells used for calcium imaging HEK293T cells transfected with 5-HT1A receptor and chimeric G ⁇ protein were used.
  • FIG. 1 is a graph showing a drug response curve with respect to a test compound concentration (log [test compound]).
  • black squares ( ⁇ ) are serotonin (5-HT)
  • triangles ( ⁇ ) are GM
  • circles ( ⁇ ) are Rinknophylline
  • white squares ( ⁇ ) are hiruthin. (Hirsutine).
  • GM was an agonist of 5-HT1A.
  • Example 3 Except that HEK293T cells transfected with 5-HT2A receptor were used for calcium imaging, the effect of the test compound (the above seven alkaloids) on 5-HT2A receptor was determined in the same manner as in Example 2. Examined. As a result, it was found that only GM among the above seven types of alkaloids has an action of inhibiting the response of 5-HT2A receptor. The results are shown in FIG.
  • FIG. 2 shows the results of examining the effect of each alkaloid on the increase in intracellular calcium concentration caused by the binding of serotonin (5-HT) to the 5-HT2A receptor.
  • the vertical axis represents the increase in intracellular calcium concentration caused by serotonin binding to the 5-HT2A receptor. That is, the decrease in the value on the vertical axis means that the binding of serotonin to the 5-HT2A receptor was inhibited.
  • the scale bar in the lower right of FIG. 2 represents 5 minutes.
  • 2-HT, GM, Rhy and Hir in the upper part of FIG. 2 mean that the cells were stimulated with a test solution containing serotonin, GM, lincofilin and hiruxtin, respectively, as shown in FIG. From FIG.
  • FIG. 3 is a graph showing an inhibition curve with respect to the GM concentration (log [GM]).
  • FIG. 3 shows that GM is an antagonist (inhibitor) of the 5-HT2A receptor.
  • Example 4 Except that HEK293T cells transfected with 5-HT2C receptor were used for calcium imaging, the effect of the test compound (the above seven alkaloids) on 5-HT2C receptor was determined in the same manner as in Example 2. Examined. As a result, it was found that only GM among the above seven types of alkaloids affects the 5-HT2C receptor, which is a serotonin receptor. The effect of GM on the 5-HT2C receptor is shown in FIG.
  • FIG. 4 is a graph showing an inhibition curve with respect to the GM concentration (log [GM]).
  • FIG. 4 shows that GM acts as an antagonist for the serotonin receptor 5-HT2C.
  • GM acted as an agonist for the 5-HT1A receptor.
  • 5-HT2A receptor it acted mainly as an antagonist and slightly as a partial agonist.
  • 5-HT2C receptor it acted as an antagonist.
  • alkaloids hiruthin and hilstein are similar in structure to GM as shown below.
  • Example 5 A test solution was prepared by dissolving GM in polyoxyethylene sorbitan monooleate.
  • a dopamine solution in which dopamine (DA) (manufactured by Sigma) was dissolved in polyoxyethylene sorbitan monooleate was used.
  • the concentration of GM or dopamine in the test solution was 1 nM to 60 ⁇ M.
  • HEK293T cells transfected with dopamine D2 receptor and chimeric G ⁇ protein were stimulated, and calcium imaging was performed according to the method described above to examine the effect of GM on dopamine D2 receptor. The results are shown in FIG.
  • FIG. 5 shows the results of examining the effect of GM on the dopamine D2 receptor.
  • the upper DA and GM in FIG. 5 mean that dopamine and GM were stimulated using the concentrations shown in FIG. 5, respectively.
  • the scale bar at the bottom right of FIG. 5 represents 5 minutes.
  • the vertical axis in FIG. 5 shows the increase in intracellular calcium concentration caused by dopamine (DA) or GM binding to the D2 receptor. That is, a large value on the vertical axis means that the D2 receptor is responding strongly.
  • GM activates the dopamine D2 receptor in a concentration-dependent manner, and since the maximum response by GM is smaller than the maximum response by dopamine stimulation, GM can act as a partial agonist on dopamine D2 receptor. I understood.
  • GM acts as an agonist for the 5-HT1A receptor of serotonin, acts as a partial agonist and antagonist for the 5-HT2A receptor, and acts on the 5-HT2C receptor.
  • corinoxein, lincophylline, isorincofilin, isocolinoxein, hilstein and hirustatin all did not affect 5-HT1A, 5-HT2A and 5-HT2C receptors at 20 ⁇ M.
  • GM acted as a partial agonist at the dopamine D2 receptor.
  • 5-HT1A receptor agonists exert an anxiolytic action
  • 5-HT2A receptor and 5-HT2C receptor antagonists act as atypical antipsychotics.
  • a partial agonist (partial agonist) of the dopamine D2 receptor functions as a dopamine-based stabilizer (Nippon Pharmacology Journal, 128: 331-345, 2006). Therefore, it has been found that GM can exert an anxiolytic action and an antipsychotic action through the action on the serotonin receptor and dopamine receptor described above, and is useful as a preventive or therapeutic agent for schizophrenia.
  • Example 6 Except that HEK293T cells transfected with 5-HT7 receptor were used for calcium imaging, the effect of the test compound (seven alkaloids described above) on 5-HT7 receptor was determined in the same manner as in Example 2. Examined.
  • the 5-HT7 receptor cDNA (GenBank Accession No. NM — 008315) is composed of the sense primer 5′-GGAGCCGAGCGGGCAAGGTGAAT-3 ′ (15-37) (SEQ ID NO: 19) and the antisense primer 5′-TGTTCTGCATTACTTCTTCTCCA-3 ′ (1470-1492).
  • HEK293T cells transfected with 5-HT7 receptor using lipofectamine were prepared.
  • the 5-HT7 receptor was loaded in Fura2 / AM for 30 minutes 24 hours after transfection.
  • the cells were placed in a chamber, and using the ArGus / Hisca system (Hamamatsu Photonics Co., Ltd.), the response elicited by administering various drugs such as serotonin and GM was measured as a change in intracellular calcium concentration.
  • 5-HT7 receptor which is a serotonin receptor.
  • the effect of GM on the 5-HT7 receptor is shown in FIG. It was revealed that GM acts as an antagonist of 5-HT7 receptor.
  • FIG. 6 is a graph showing an inhibition curve of serotonin receptor 5-HT7 with respect to GM concentration (log [GM]).
  • FIG. 6 shows that GM acts as an antagonist for the serotonin receptor 5-HT7.
  • the preventive or therapeutic agent of the present invention is useful in the medical field because it has few side effects and can prevent or treat schizophrenia.

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Abstract

L'invention porte sur un agent prophylactique ou thérapeutique pour la schizophrénie, comprenant de la geissoschizine méthyléther comme ingrédient actif.
PCT/JP2011/050124 2010-01-07 2011-01-06 Agent prophylactique ou thérapeutique pour la schizophrénie WO2011083823A1 (fr)

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Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
KANATANI, H. ET AL.: "The active principles of the branchlet and hook of Uncaria sinensis Oliv. examined with a 5-hydroxytryptamine receptor binding assay", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 37, no. 6, 1985, pages 401 - 404 *
KINJI MATSUMOTO: "Choto-san no Ko Chiho Koka -sono Jikken Yakurigakuteki Urazuke", WAKAN'YAKU, no. 617, 2004, pages 2 - 3 *
PENGSUPARP, T. ET AL.: "Pharmacological studies of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., in the central nervous system", EUR J PHARMACOL, vol. 425, no. 3, 2001, pages 211 - 218 *
YASUHIRO KOMATSU: "Choto-san no Kiso Yakurigakuteki Kenkyu", KOSEI-SHO KOSEI KAGAKU KENKYUHI HOJOKIN CHOJU KAGAKU SOGO KENKYU HEISEI 8 NENDO KENKYU HOKOKU, vol. 9, 1997, pages 75 - 78 *
YUZURIHARA, M. ET AL.: "Geissoschizine methyl ether, an indole alkaloid extracted from Uncariae Ramulus et Uncus, is a potent vasorelaxant of isolated rat aorta", EUR J PHARMACOL, vol. 444, no. 3, 2002, pages 183 - 189 *
ZHANG, S. ET AL.: "Protective effect of Choto- san, Chotoko and its alkaloids on experimental vascular dementia in mice : Elucidation using Morris water maze test", J TRADIT MED, vol. 19, no. 1, 2002, pages 28 - 36 *

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