WO2009093671A1 - Agent antidépresseur/anxiolytique - Google Patents

Agent antidépresseur/anxiolytique Download PDF

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Publication number
WO2009093671A1
WO2009093671A1 PCT/JP2009/051027 JP2009051027W WO2009093671A1 WO 2009093671 A1 WO2009093671 A1 WO 2009093671A1 JP 2009051027 W JP2009051027 W JP 2009051027W WO 2009093671 A1 WO2009093671 A1 WO 2009093671A1
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WO
WIPO (PCT)
Prior art keywords
ile
leu
peptide
anxiety
active ingredient
Prior art date
Application number
PCT/JP2009/051027
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English (en)
Japanese (ja)
Inventor
Atsumi Nitta
Yoko Hibi
Toshitaka Nabeshima
Koji Morishita
Takeshi Ikeda
Original Assignee
Kyowa Hakko Bio Co., Ltd.
National University Corporation Nagoya University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Bio Co., Ltd., National University Corporation Nagoya University filed Critical Kyowa Hakko Bio Co., Ltd.
Publication of WO2009093671A1 publication Critical patent/WO2009093671A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid

Definitions

  • the present invention relates to an antidepressant and anxiolytic agent effective in suppressing and improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • Tricyclic antidepressants such as imipramine were widely used as treatments for depression, but these have strong unpleasant side effects due to anticholinergic effects such as dry mouth, blurred vision, urinary retention, and constipation. It is known.
  • selective serotonin reuptake inhibitors with reduced side effects and serotonin and noradrenaline reuptake inhibitors have been put on the market, and the options for drug treatment for depression are expanding.
  • side effects such as sexual dysfunction and gastrointestinal disorders have been pointed out, and it is not suitable for long-term use or preventive use of the elderly. Therefore, a new type of antidepressant that has no side effects and high safety is desired.
  • benzodiazepine-based drugs are widely used as anxiolytic drugs, but when taken over a long period of time, side effects such as tolerance, mental and physical dependence may occur. Alternatively, even when taken in a small amount or for a short period of time, side effects such as drowsiness, reduced behavioral ability, and ataxia may occur, and there is a need to develop a highly safe anxiolytic agent that has no side effects.
  • Non-Patent Document 1 Non-Patent Document 1
  • BDNF brain-derived neurophic factor
  • Non-patent Document 2 glial cell line-derived neurophic factor
  • Akt Akt involved in the regulation of GDNF production
  • JP-A-2005-41834 WO / 2006/090555 Nitta A. et al., Folia Pharmacologica Japonica, 122: 81-83 (2003) Nitta A et al .. J Neurosci. Res., 78: 250-258 (2004)
  • An object of the present invention is to provide a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • the present inventors have found that the dipeptide Leu-Ile, which has significantly different physical properties and chemical structures from conventional representative antidepressants or anxiolytic agents, such as depression and anxiety.
  • the present inventors have found that it is effective in suppressing and improving psychiatric symptoms, and have completed the present invention.
  • the present invention has been obtained from the above knowledge and has the following configuration.
  • An antidepressant comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • An anxiolytic agent comprising a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • a method for preventing or treating depression or anxiety comprising the step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
  • peptides are expressed according to a conventional notation so that the left end is the amino terminus and the right end is the carboxyl terminus.
  • the amino acid residue is L-form
  • the indication that it is L-form is omitted.
  • the present invention provides a novel antidepressant and anxiolytic agent effective in suppressing or improving psychiatric symptoms caused by stress and the like, particularly depression and anxiety symptoms.
  • 6 is a graph showing measurement results of immobility time by a forced swimming test of Test Example 1. It is a graph which shows the measurement result of the open arm stay time by the elevated plus maze test of Test example 2. 6 is a graph showing the results of the number of new neurons in the hippocampal dentate gyrus of Test Example 3.
  • examples of the peptide consisting of Leu and Ile include Leu-Ile and Ile-Leu, but Leu-Ile is preferably used.
  • a peptide consisting of Leu and Ile or a modified form thereof is a part of the basic structure (dipeptide) consisting of Leu and Ile (may be a plurality of positions) with other atomic groups or the like.
  • a compound having a structure different from the basic structure is shown at least in part by modification such as substitution or addition of another molecule.
  • a peptide obtained by substituting at least one of Leu and Ile in a dipeptide with a D-form or DL-form is also included in a peptide comprising Leu and Ile or a modified form thereof.
  • a peptide derivative in which a part of the side chain of Leu or Ile is substituted with another atom or atomic group can be mentioned.
  • Other atoms or atomic groups herein include a hydroxyl group, halogen (fluorine, chlorine, bromine, iodine, etc.), alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, etc.), hydroxyalkyl group ( Examples thereof include hydroxymethyl group, hydroxyethyl group, etc., alkoxy groups (methoxy group, ethoxy group, etc.), acyl groups (formyl group, acetyl group, malonyl group, benzoyl group, etc.) and the like.
  • the modified peptide of the present invention includes those in which the functional group of Leu or Ile is protected by an appropriate protecting group.
  • an acyl group, an alkyl group, a monosaccharide, an oligosaccharide, a polysaccharide and the like can be used.
  • Such a protecting group is linked by an amide bond, an ester bond, a urethane bond, a urea bond, or the like according to the peptide site to which the protecting group is bound, the kind of the protecting group to be used, or the like.
  • modified peptide of the present invention one modified by addition of a sugar chain can be mentioned.
  • various peptide derivatives classified into alkylamine, alkylamide, sulfinyl, sulfonylamide, halide, amide, aminoalcohol, ester, aminoaldehyde, etc. by replacing the N-terminal or C-terminal with other atoms etc. Included in the modified peptides of the invention.
  • a peptide derivative constituted by combining the various modification methods described above may be used as the modified peptide of the present invention.
  • the peptide of Leu and Ile according to the present invention or a modified form thereof includes a salt of the peptide, a salt of the modified peptide or a hydrate thereof.
  • the salt of the present invention is not particularly limited as long as it is pharmaceutically acceptable, and is a salt (inorganic acid salt) with hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, boric acid or the like, formic acid, acetic acid, lactic acid, fumaric acid Examples thereof include salts (organic acid salts) with maleic acid, tartaric acid, citric acid and the like. These salts can be prepared by conventional means.
  • dietary supplements include oral preparations that have the same shape as pharmaceuticals but do not belong to pharmaceuticals under the Pharmaceutical Affairs Law, or those obtained by adding the active ingredient of the present invention to foods.
  • the present invention corresponds to a pharmaceutical composition or a dietary supplement nutrition composition containing a peptide comprising Leu and Ile or a modified product thereof as an active ingredient.
  • the pharmaceutical preparation means a carrier usually used as a pharmaceutical preparation base for the active ingredient of the present invention, such as an excipient, a disintegrant, a lubricant, a buffering agent, a binder, an emulsifier, a suspending agent, and a soothing agent.
  • a carrier usually used as a pharmaceutical preparation base for the active ingredient of the present invention, such as an excipient, a disintegrant, a lubricant, a buffering agent, a binder, an emulsifier, a suspending agent, and a soothing agent.
  • an excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • starch carboxymethylcellulose, calcium carbonate and the like
  • Phosphate, citrate, acetate, etc. can be used as the buffer.
  • emulsifier gum arabic, sodium alginate, tragacanth and the like can be used.
  • binder pullulan, gum arabic, gelatin, starch or the like can be used.
  • lubricant magnesium stearate, methylcellulose, or magnesium silicate can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • stabilizer propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • the dietary supplement oral preparation in the present invention is a carrier that is usually used as a base for a nutritional food preparation for the active ingredient of the present invention, such as an excipient, a disintegrant, an emulsifier, a stabilizer, a lubricant, a buffer, a fragrance.
  • the dosage form includes tablets, powders, fine granules, granules, and capsules.
  • Examples of dietary supplements obtained by adding the active ingredient of the present invention to foods include nutritional drinks, soft drinks, jelly, and the like produced by the conventional method using the active ingredient of the present invention.
  • a peptide comprising Leu and Ile can be produced by a known peptide synthesis method (for example, solid phase synthesis method, liquid phase synthesis method). However, when the peptide of the present invention exists in nature, it can also be prepared by operations such as extraction and purification. Examples of sources for obtaining the peptide of the present invention include animal cells (including humans), plant cells, body fluids (blood, urine, etc.).
  • a modified form of a peptide consisting of Leu and Ile can be produced by a conventional method as described above.
  • compositions or oral dietary supplement preparations containing modified peptides of Leu and Ile as active ingredients should be produced according to conventional methods using the obtained modified peptides of Leu and Ile as the main active ingredients. Can do.
  • other pharmaceutically acceptable ingredients for example, carriers, excipients, disintegrants, buffers, emulsifiers, binders, lubricants, suspending agents, soothing agents, stabilizers, Preservatives, preservatives, physiological saline, and the like
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used. Phosphate, citrate, acetate, etc. can be used as the buffer.
  • gum arabic sodium alginate, tragacanth and the like
  • binder pullulan, gum arabic, gelatin, starch or the like
  • lubricant magnesium stearate, methylcellulose, or magnesium silicate can be used.
  • suspending agent glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • soothing agent benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • propylene glycol, diethylin sulfite, ascorbic acid or the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like can be used.
  • preservatives benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • desired dosage forms such as tablets, powders, fine granules, granules, capsules, syrups, injections, external preparations, and suppositories can be produced by conventional methods.
  • modified foods of peptides consisting of Leu and Ile can be added to produce nutritional foods such as nutritional drinks, soft drinks, and jelly by conventional methods.
  • the antidepressant and anxiolytic agent comprising the thus obtained Leu and Ile peptide of the present invention or a modified product thereof as an active ingredient is administered orally or parenterally (intravenous, intraarterial, (Subcutaneous, intramuscular, intraperitoneal injection, etc.).
  • the content of active ingredients (peptides, etc.) in the drug of the present invention generally varies depending on the dosage form, but in the case of liquid preparations such as injections, it is about 0.001% to about 10% by weight, preferably 0.01% to about 3% by weight. Particularly preferably, it is 0.1% by weight to about 1% by weight. In the case of a solid preparation such as a tablet, 0.1% by weight to about 90% by weight, preferably 1% by weight to about 50% by weight, particularly preferably 3% by weight to about 1% by weight. 30% by weight.
  • the treatment method or prevention method of the present invention includes a step of administering to a living body a preparation comprising a peptide comprising Leu and Ile or a modified form thereof as an active ingredient.
  • the administration route is not particularly limited, and examples thereof include oral, intravenous, intradermal, subcutaneous, intramuscular, intraperitoneal, transdermal, and transmucosal.
  • the dose of the drug varies depending on symptoms, patient age, sex, weight, and the like, but those skilled in the art can appropriately set an appropriate dose.
  • the amount of active ingredient per day for an adult is about 0.1 ⁇ g to about 3000 kg, preferably about 0.1 mg to about
  • the dose can be set to 2000 mg, particularly preferably about 0.1 mg to about 1000 mg.
  • the administration schedule for example, once to several times a day, once every two days, or once every three days can be adopted.
  • a method for preventing depression (anxiety) and anxiety (anxiety symptoms) by administering a preparation comprising a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient is the expression of symptoms of depression and anxiety
  • non-adult adults take prophylactic preparations containing a peptide consisting of Leu and Ile or a modified form thereof as an active ingredient.
  • a method of treating depression and anxiety by administering a preparation comprising a peptide comprising Ile or a modified form thereof as an active ingredient is a method for suppressing or preventing progression of depression and anxiety in a patient who has developed symptoms of depression or anxiety Indicates administration to improve. In setting the administration schedule, it is possible to take into account the patient's medical condition and the duration of the drug effect.
  • depression or “depression” according to the present invention is a kind of mood disorder, depressed mood, decreased motivation, loss of interest and joy, reduced concentration and attention, self-evaluation and reduced confidence It means psychiatric symptoms or diseases characterized by guilt and worthlessness, pessimism about the future, suicidal ideation, sleep disorders, and anorexia. In clinical settings, it is often treated as depression that has a certain degree of severity in the DSM diagnostic criteria, which is “other than bereavement reaction, lasts every day for more than 2 weeks and presents functional impairment of life”. However, in the present invention, without being bound by such diagnostic criteria, depression associated with transient psychological stress (adaptation disorder, acute stress disorder, PTSD, etc.), schizophrenia, panic disorder, etc. It is intended to broadly encompass diseases or symptoms associated with depression, such as depression and endogenous depression as symptoms of other diseases.
  • anxiety or “anxiety symptom” is a psychiatric symptom or disease whose main symptom is anxiety (a kind of emotion that occurs when the self cannot cope with fear without a clear target). It means general and may manifest as physical symptoms such as sweating, palpitation, tachycardia, chest pain, headache, diarrhea as well as behavioral and psychological disorders.
  • the “anxiety” includes phobic anxiety disorder (square fear, social phobia (social anxiety disorder), interpersonal phobia), panic disorder, irritable bowel syndrome, generalized anxiety disorder, mixedness Anxiety is a major symptom, such as anxiety-depressive disorder, obsessive-compulsive disorder, severe stress response and adjustment disorder (PTSD, acute stress disorder, adjustment disorder), general physical anxiety disorder, substance-induced anxiety disorder, unspecified anxiety disorder It is intended to encompass a wide range of diseases or symptoms.
  • the antidepressant action and anxiolytic action of the present invention can be confirmed by a forced swimming test method using a mouse and an elevated plus maze test, as described below.
  • the forced swimming test method is the most widely used method for evaluating antidepressants in animals, and clinically effective antidepressants are known to shorten immobility time (Porsortet al. Nature 266, 730-732, 1977).
  • the elevated plus maze test is commonly used as an anxiolytic evaluation method. When anxiety is reduced by the administration of anxiolytics, the time spent on a runway with no walls (open arm) is extended. (Pellow et al., Pharmacol, Biochem, Behav., 24, 525-529, 1986).
  • Leu-Ile 750 ⁇ mol / Kg was orally administered to the Leu-Ile administration group using an oral sonde. Forced swimming and dosing were performed for 2 weeks. Statistical analysis was performed by analysis of variance (determined that there was a significant difference at a significance level of less than 5%), and the antidepressant action of Leu-Ile was measured.
  • Figure 1 shows the result of the immobility time.
  • the immobility time was significantly shortened on the 14th day compared to the control group. From these results, it was revealed that Leu-Ile has an antidepressant action.
  • Brodeoxyuridine (BrdU) 75 mg / Kg was intraperitoneally administered three times every 3 hours on the last day. The remaining 1 group was not loaded with forced swimming, and BrdU was administered at the same timing as the other 2 groups (forced swimming unloaded group).
  • the results of the number of new neurons in the hippocampal dentate gyrus are shown in FIG.
  • the control group showed a significant decrease in the number of BrdU positive cells compared to the forced swimming no-load group.
  • the Leu-Ile administration group showed a significant increase in the number of BrdU positive cells compared to the control group. From these results, it was revealed that Leu-Ile promotes the neurogenesis of neurons.
  • Example 1 Tablets Tablets having the following composition are prepared by a conventional method.
  • the present invention can be used in the pharmaceutical and food fields as a pharmaceutical composition and a nutritional composition for dietary supplements for the purpose of preventing or treating depression or anxiety.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'invention concerne un nouvel agent antidépresseur et anxiolytique efficace pour la prévention ou l'amélioration d'un état mental induit par le stress ou par un effet similaire, en particulier un état dépressif ou anxieux. Cet agent antidépresseur et anxiolytique comprend un peptide comprenant Leu et Ile ou un produit modifié de celui-ci comme principe actif.
PCT/JP2009/051027 2008-01-24 2009-01-23 Agent antidépresseur/anxiolytique WO2009093671A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011077760A1 (fr) * 2009-12-25 2011-06-30 Suntory Holdings Limited Améliorateurs de la motivation de l'apprentissage
JP2014162735A (ja) * 2013-02-22 2014-09-08 Kyoto Univ 抗うつ剤又は抗不安剤

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61501568A (ja) * 1984-03-01 1986-07-31 ア−ク，バ−ノン 脊椎動物の抑うつの治療方法
JP2005041834A (ja) * 2003-07-24 2005-02-17 Nagoya Industrial Science Research Inst 抗薬物依存形成剤
WO2006090555A1 (fr) * 2005-02-25 2006-08-31 National University Corporation Nagoya University Agent d'activation de akt

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61501568A (ja) * 1984-03-01 1986-07-31 ア−ク，バ−ノン 脊椎動物の抑うつの治療方法
JP2005041834A (ja) * 2003-07-24 2005-02-17 Nagoya Industrial Science Research Inst 抗薬物依存形成剤
WO2006090555A1 (fr) * 2005-02-25 2006-08-31 National University Corporation Nagoya University Agent d'activation de akt

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
MERCADO, M.L.: "Functional peptide sequences derived from extracellular matrix glycoproteins and their receptors: Strategies to improve neuronal regeneration", MOLECULAR NEUROBIOLOGY, vol. 27, no. 2, 2003, pages 177 - 195 *
NITTA, A. ET AL.: "Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis", J NEUROSCI RES, vol. 78, no. 2, 2004, pages 250 - 8 *
YOKO HIBI ET AL.: "Kyosei Suiei ni yotte Yudo sareru Utsuyo Shojo ni Taisuru Leu-Ile no Koka", NIPPON YAKUGAKUKAI NENKAI YOSHISHU, vol. 128, no. 3, 5 March 2008 (2008-03-05), pages 12 *
YOKO HIBI ET AL.: "Roka ni Tomonau Ninchisho ni Yuko na Shinkei Hogoyaku no Rinsho Oyo to sono Hyokaho no Kakuritsu", CHOJU KAGAKU SOGO KENKYU SUISHIN JIGYO KENKYU HOKOKUSHU HEISEI 19 NENDO, 2008, pages 177 - 180 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011077760A1 (fr) * 2009-12-25 2011-06-30 Suntory Holdings Limited Améliorateurs de la motivation de l'apprentissage
JP2012517998A (ja) * 2009-12-25 2012-08-09 サントリーホールディングス株式会社 学習意欲改善剤
GB2488500A (en) * 2009-12-25 2012-08-29 Suntory Holdings Ltd Learning motivation improvers
CN102665717A (zh) * 2009-12-25 2012-09-12 三得利控股株式会社 学习积极性改善剂
GB2488500B (en) * 2009-12-25 2013-04-24 Suntory Holdings Ltd Substances for use as anti-depressants or as a learning motivation improver
CN102665717B (zh) * 2009-12-25 2014-10-29 三得利控股株式会社 学习积极性改善剂
US9623073B2 (en) 2009-12-25 2017-04-18 Suntory Holdings Limited Learning motivation improvers
JP2014162735A (ja) * 2013-02-22 2014-09-08 Kyoto Univ 抗うつ剤又は抗不安剤

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