WO2011148972A1 - Composition pharmaceutique contenant un peptide biologiquement actif - Google Patents

Composition pharmaceutique contenant un peptide biologiquement actif Download PDF

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Publication number
WO2011148972A1
WO2011148972A1 PCT/JP2011/061965 JP2011061965W WO2011148972A1 WO 2011148972 A1 WO2011148972 A1 WO 2011148972A1 JP 2011061965 W JP2011061965 W JP 2011061965W WO 2011148972 A1 WO2011148972 A1 WO 2011148972A1
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Prior art keywords
peptide
yvlsr
anxiolytic
receptor
acid
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PCT/JP2011/061965
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English (en)
Japanese (ja)
Inventor
耕作 大日向
千尋 鈴木
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独立行政法人科学技術振興機構
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Publication of WO2011148972A1 publication Critical patent/WO2011148972A1/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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a pharmaceutical composition that acts on the nervous system.
  • the present invention also relates to a peptide or an analog thereof, and more specifically, a peptide that activates at least one of a ⁇ opioid receptor, a 5-HT 1A receptor, a D 1 receptor, and a GABA A receptor or an analog thereof.
  • the present invention relates to a food for improving anxiety or sleep.
  • anxiolytic compound can be produced inexpensively and is preferably effective by oral administration.
  • the purpose is to supply drugs and foods that have anti-anxiety action, antidepressant action, etc. even with relatively low doses and few side effects.
  • the present inventors have studied the emotion-regulating action of various food protein-derived peptides, and Tyr-Val-Leu-Ser-Arg derived from milk ⁇ -casein exhibits an anxiolytic action.
  • the present inventors have found that the ⁇ 1 receptor, 5-HT 1A receptor, D 1 receptor, or GABA A receptor is activated downstream of the ⁇ receptor, thereby completing the present invention.
  • Item 1 A pharmaceutical composition comprising a peptide represented by YVLSR (SEQ ID NO: 1) or an analog thereof as an active ingredient.
  • Item 2. The pharmaceutical composition according to Item 1, which is an anxiolytic agent, sleep-inducing agent, sleep-improving agent, schizophrenia therapeutic agent or antidepressant.
  • Item 3 An anti-anxiety or sleep improving food containing a peptide represented by YVLSR or an analog thereof.
  • Item 4 A peptide represented by YVLSR or an analog thereof.
  • Item 5 A peptide represented by YVLSR or an analog thereof for anxiety, sleep induction, sleep improvement, schizophrenia treatment or antidepressant.
  • Item 6 A method for anxiety, sleep induction, sleep improvement, schizophrenia treatment or antidepressant, comprising the step of administering the pharmaceutical composition according to item 1 or 2 to a patient.
  • the pharmaceutical composition and food of the present invention exhibit high anti-anxiety action, antidepressant action, etc., even at a relatively low dose, as peptides contained therein or their analogs. Moreover, the peptides contained in the pharmaceutical composition and food of the present invention are derived from food proteins with abundant food experience, and it can be expected that there are few side effects.
  • the present inventors are currently trying to identify a receptor to which this peptide directly binds, but if the target receptor of YVLSR, which is a very potent anxiolytic peptide, is clarified, a novel anxiolytic mechanism will be developed. Not only can it be elucidated, it can be a target for new drug discovery.
  • ⁇ Anorexia in the elderly is known to promote aging.
  • endogenous feeding stimulating peptides such as NPY and ghrelin were administered intraventricularly or intravenously, feeding stimulating effects were observed, but there were no reports of effective feeding stimulating peptides by oral administration.
  • the amount of food consumed in mice after oral administration 0.3 mg / kg
  • the delta opioid peptide rubiscolin-6 derived from Rubisco which is a major protein of green leaves and is known as the most abundant protein on earth.
  • ⁇ opioid has both a learning promoting action and an anxiolytic action. Therefore, the anti-anxiety peptide YVLSR that activates the ⁇ opioid receptor is expected to have a feeding-promoting action and a learning-promoting action, and may be used as a material for food for the elderly.
  • Rubisocolin-6 has recently been found to promote normal food intake while suppressing high-fat food intake as described above, and ⁇ opioid receptors have been shown to be involved in normalizing food preferences .
  • the YVLSR and its analogs of the present invention may also have a preference normalization ability.
  • the anxiolytic action is developed as an anxiety-related behavior evaluation method for screening an anxiolytic drug, and can be evaluated by an elevated plus maze test (FIG. 1). Specifically, an anxiolytic candidate substance is administered orally or intraperitoneally, and after 30 minutes, the mouse is placed in the elevated plus maze, and the change in the number of intrusions into the open arm and the staying time on the open arm is indicated. As described above, the strength of the anti-anxiety action can be evaluated.
  • YVLSR showed no affinity for the ⁇ receptor and also no ⁇ opioid activity using mouse vas deferens (MVD). From the above results, it is considered that YVLSR activates the central ⁇ receptor by promoting the release of endogenous ⁇ opioid ligand.
  • the anxiolytic action of the peptide which is the active ingredient of the medicament of the present invention is inhibited by antagonists to ⁇ 1 , serotonin 5-HT 1A , dopamine D 1 , and GABA A receptor. There was no affinity for the receptor. Therefore, the anxiolytic effect of YVLSR is through the release of neurotransmitters such as endogenous ⁇ 1 ligand, serotonin, dopamine, GABA and the activation of ⁇ 1 , 5-HT 1A , D 1 , and GABA A receptors. (Fig. 8).
  • a preferable route of administration of the peptide of the present invention or an analog thereof is oral administration.
  • the active ingredient of the anxiolytic agent of the present invention is a peptide represented by Y (Tyr) -V (Val) -L (Leu) -S (Ser) -R (Arg) or an analog thereof.
  • the amino acids constituting the peptide are L-form amino acids, D-form amino acids, or DL-form amino acids (if the D-form and L-form amino acids are mixed, the racemic form and any amino acid in which one of the enantiomers is excessive) Included).
  • Preferable is a peptide consisting only of L-form amino acids or only D-form amino acids, particularly a peptide consisting only of L-form amino acids.
  • the peptide used in the present invention when it contains two or more asymmetric carbons, it may be in the form of each enantiomer or diastereomer or a mixture of these in any ratio. Separation of enantiomers or diastereomers may be carried out using a normal column, or an optically active column is used, or an optically active group is introduced and optically resolved in the form of a derivative, and then the optically active group is removed. Alternatively, any known method such as optical resolution by forming a salt with an optically active acid or base may be used.
  • salts of peptides or analogs thereof include acid addition salts and base salts.
  • Acid addition salts include inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid, citric acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, p-toluenesulfonic acid And salts of organic acids such as benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.
  • the base salt include alkali metal salts such as sodium, potassium and lithium, and alkaline earth metal salts such as calcium and magnesium.
  • Solvates include solvates such as water (in the case of hydrates), methanol, ethanol, isopropanol, acetic acid, tetrahydrofuran, acetone, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, acetamide, ethylene glycol, propylene glycol, and dimethoxyethane. Things.
  • the active ingredient of the pharmaceutical composition and food according to the present invention not only the above peptides but also various peptide analogs can be used as long as a desired pharmacological effect is obtained.
  • the peptide active ingredient is a peptide analog
  • the peptide analog includes (1) N-terminal modification and (2) C-terminal modification analogs of the peptide of the active ingredient.
  • the N-terminal amino group of the peptide is linear or branched carbon such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, n-butylamino, di-n-butylamino, etc. It may be an amino group mono- or di-substituted with an alkyl group of 1 to 4.
  • the N-terminal amino group or the side chain amino group may be mono- or di-substituted with an aralkyl group such as a benzyl group or a phenethyl group, a formyl group, an acetyl group, or a propionyl group And may be modified with a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as a butyryl group or an isobutyryl group, or an acyl group such as a benzoyl group.
  • an aralkyl group such as a benzyl group or a phenethyl group, a formyl group, an acetyl group, or a propionyl group
  • a linear or branched alkanoyl group having 1 to 6 carbon atoms such as a butyryl group or an isobutyryl group
  • an acyl group such as a benzoyl group.
  • the carboxyl group at the C-terminal of the peptide is an ester with a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, benzyl , Esters with aralkyl groups such as phenethyl, amino groups, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, n-butylamine, di-n-butylamine, etc.
  • An amine mono- or di-substituted with 4 alkyl groups or an amide with ammonia may be formed.
  • the peptide of the present invention can be obtained by hydrolysis of a natural protein or polypeptide, or can be obtained by chemical synthesis.
  • Examples of the protein or polypeptide to be hydrolyzed include casein derived from milk or human milk. These peptides derived from food materials can be used as they are, or as they are, as they are, by carrying out treatments such as concentration, desalting and purification as necessary.
  • Examples of protein hydrolysis include the use of hydrolytic enzymes derived from animals, plants or microorganisms such as trypsin, chymotrypsin, papain, pepsin, carboxypeptidase, thermolysin, and subtilisin. Accordingly, the peptide of the active ingredient of the present invention can be obtained by adjusting to an appropriate value and reacting at a temperature of about 20 to 40 ° C. for about 30 minutes to 48 hours.
  • YVLSR is partially generated by further digesting casoxin C generated by trypsin digestion of ⁇ -casein with pepsin.
  • the peptide of the present invention may be purified from the obtained reaction solution, and when the food material is enzymatically decomposed, it can be used as it is or added to another food material to form a food or a food composition.
  • Hydrolysis can be performed using strong acids (for example, hydrochloric acid, nitric acid, sulfuric acid, etc.) or strong bases (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, carbonates).
  • the peptide of the active ingredient of the present invention can be obtained by reacting in water at a temperature of 1 to 100 ° C. for 30 minutes to 48 hours in the presence of an alkali metal hydrogen carbonate such as sodium hydrogen or potassium hydrogen carbonate). It can.
  • the reaction product of the hydrolysis may be used as it is after the pH is adjusted, or the peptide of the active ingredient may be separated and used by purification.
  • the peptide of the present invention can also be obtained by peptide synthesis. That is, in a liquid phase method or a solid phase method, which is a commonly used method for peptide synthesis, a raw material having a reactive carboxyl group and a raw material having a reactive amino group are combined with a method using an active ester such as HBTU, or carbodiimide In a peptide synthesis such as a method using a coupling agent such as When the resulting condensate has a protecting group, it can also be produced by removing the protecting group.
  • the C-terminal carboxyl group is a chlorotrityl resin, chloromethyl resin, oxymethyl resin, p- It is bound to a carrier such as an alkoxybenzyl alcohol resin.
  • the condensation reaction is performed in the presence of a condensing agent such as carbodiimide or using an N-protected amino acid active ester or peptide active ester.
  • the protecting group is removed, but in the case of the solid phase method, the bond between the C-terminus of the peptide and the resin is further cleaved.
  • the peptides of the present invention are purified according to conventional methods. Examples thereof include ion exchange chromatography, reverse phase liquid chromatography, affinity chromatography and the like.
  • the synthesized peptide is analyzed by a protein sequencer that reads the amino acid sequence from the C-terminal by Edman degradation, LC-MS, GC-MS, or the like.
  • the peptide of the present invention can also be synthesized by an enzymatic method (see WO2003 / 010307).
  • the administration route of the peptide of the present invention is not particularly limited, and any of oral administration, parenteral administration, and rectal administration can be adopted, and it can be administered orally or parenterally.
  • the dosage of this peptide varies depending on the type of compound, the administration method, the condition and age of the administered person, etc., but is usually 0.001 to 500 mg / kg, preferably 0.005 to 100 mg / kg per day for an adult. More preferably, it is 0.01 to 30 mg / kg.
  • the peptide (active ingredient) of the present invention is usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
  • a pharmaceutical carrier a substance that is commonly used in the pharmaceutical field and does not react with the peptide of the present invention is used.
  • the peptide of the present invention can be used as a food or a medicine per se, or alone or together with a suitable non-toxic carrier for ingestion, diluent or excipient (tablet, uncoated tablet, dragee, effervescent tablet, Film-coated tablets, chewable tablets, etc.), capsules, troches, powders, fine granules, granules, solutions, suspensions, emulsions, pastes, creams, injections (amino acid infusions, electrolyte infusions, etc.) Or a preparation for food or medicine such as sustained release preparations such as enteric tablets, capsules and granules.
  • the content of the peptide in the food can be appropriately selected, but is generally in the range of 0.01 to 100% by weight.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, injections, and the like. These preparations are prepared according to a conventional method.
  • the liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method.
  • injection it is prepared by dissolving the peptide of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good.
  • These preparations may contain the peptide of the present invention in a proportion of 0.01% to 100% by weight, preferably 1 to 90% by weight. These formulations may also contain other therapeutically valuable ingredients.
  • an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules.
  • these powders and granules may be tableted as they are or with the addition of lubricants such as magnesium stearate and talc.
  • granules or tablets should be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate, methacrylic acid-methyl methacrylate polymer, etc., and coated with an enteric solvent preparation, or with ethylcellulose, carnauba wax, hardened oil, etc. You can also.
  • an enteric solvent base such as hydroxypropylmethylcellulose phthalate, methacrylic acid-methyl methacrylate polymer, etc.
  • enteric solvent preparation or with ethylcellulose, carnauba wax, hardened oil, etc.
  • an active ingredient and a sweetener such as sucrose, sorbitol, and glycerin are dissolved in water to add a transparent syrup, further essential oil, ethanol, etc. to make an elixir, Gum arabic, tragacanth, polysorbate 80, sodium carboxymethyl cellulose and the like may be added to form an emulsion or suspension.
  • a transparent syrup such as sucrose, sorbitol, and glycerin
  • active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, pH adjusters, sodium chloride, glucose etc.
  • active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, pH adjusters, sodium chloride, glucose etc.
  • Dissolve in distilled water for injection with an isotonic agent filter aseptically and fill into ampoules, or add mannitol, dextrin, cyclodextrin, gelatin, etc. Good.
  • lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to give an emulsion for injection.
  • the active ingredient is moistened with a suppository base such as cacao butter, fatty acid tri, di and monoglycerides, polyethylene glycol, etc., poured into a mold and cooled,
  • a suppository base such as cacao butter, fatty acid tri, di and monoglycerides, polyethylene glycol, etc.
  • the active ingredient may be dissolved in polyethylene glycol, soybean oil, etc. and then covered with a gelatin film.
  • the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to make an ointment, or rosin, alkyl acrylate polymer After being kneaded with an adhesive such as polyalkyl, it is spread on a non-woven fabric such as polyalkyl to obtain a tape.
  • beverages coffee, cocoa, juice, soft drinks, mineral drinks, tea drinks, green tea, tea, oolong tea, and milk drinks.
  • Lactic acid bacteria beverage yogurt beverage, carbonated beverage
  • gum gummi
  • jelly candy
  • cookies crackers
  • biscuits ice confectionery (ice cream, ice candy, sorbet, shaved ice, etc.)
  • retort food jelly-like food (je
  • Foods that can be prepared by adding and blending the peptides of the present invention include so-called health foods, functional foods, dietary supplements, supplements, foods for specified health use, combined foods for the sick and the sick (Ministry of Health, Labor and Welfare) , Special-purpose foods) or elderly foods (Ministry of Health, Labor and Welfare, special-purpose foods), uncoated tablets, film-coated tablets, dragees, granules, powders, tablets, capsules (both hard capsules and soft capsules) Including chewable type, syrup type, and drink type.
  • the preparation of food containing the peptide according to the present invention can be carried out by a method known per se.
  • Peptide YVLSR was synthesized by solid phase by Fmoc method, purified using reverse phase HPLC, and further freeze-dried. Male ddY mice were used as experimental animals. The anxiolytic activity was measured by the elevated plus maze test and the open field test described below. The result of the mass spectrum of peptide YVLSR is shown below. Ion Measured value Theoretical value [YVLSR + H] 637.39 637.37 [YVLSR + 2H] 319.20 319.19
  • the elevated plus maze (EPM) consists of two open arms (25cm x 5cm) and two closed arms (25cm x 5cm x 15cm), which are off the floor Combined with the central platform raised 50 cm (see Figure 1).
  • EPM elevated plus maze
  • the periphery of the open arm is open and there are no walls, the mouse walking on the open arm feels uneasy that the mouse falls from a high position. For this reason, the longer the mouse stays in the open arm or the greater the number of times of entry, the less the anxiety of the mouse, which becomes an index of anxiolytic activity.
  • the test was started by placing the mouse on the central platform facing one of the open arms. Cumulative time spent in open arms (time in open arms), number of visits to open arms (visit to open arms), total number of visits to any arm (total visits) was recorded. The percentage of time spent in the open arm and the percentage of visits to the open arm were calculated as an indicator of anxiety.
  • the peptide when administered into the ventricle, it was administered 20 minutes before the test, and when administered intraperitoneally and orally, 30 minutes before the test.
  • the open field used in this experiment is a cylindrical gray device with a diameter of 60 cm and a height of 50 cm, divided into 25 sections by black lines.
  • the mouse performs a search action when placed in a new environment, but normally, there are few searches to the center of the device. However, treatment with anxiolytics increases the time spent in the center circle and the number of entries. Thirty minutes after the administration of the peptide, the mouse was placed in the center of the apparatus and the behavior was observed for 5 minutes.
  • YVLSR Central ⁇ receptor activation by YVLSR
  • the anxiolytic effect of YVLSR by oral administration was inhibited by intracerebroventricular administration (10 nmol / mouse) of the ⁇ opioid receptor antagonist naltrindole (FIG. 5).
  • the ⁇ antagonist naloxone was not inhibited (data not shown).
  • YVLSR showed no affinity for the ⁇ receptor and also no ⁇ opioid activity using mouse vas deferens (MVD). From the above results, it is considered that YVLSR activates the central ⁇ receptor by promoting the release of endogenous ⁇ opioid ligand.
  • the anxiolytic effect of YVLSR is through the release of neurotransmitters such as endogenous ⁇ 1 ligand, serotonin, dopamine, GABA and the activation of ⁇ 1 , 5-HT 1A , D 1 , and GABA A receptors. It became clear that. As a preliminary study, the anxiolytic effect of the specific ⁇ agonist DPDPE is inhibited by antagonists to ⁇ 1 , 5-HT 1A , D 1 , and GABA A receptors, and is consistent with the anxiolytic pathway of YVLSR.
  • YVLSR exhibits an anxiolytic effect upon intraventricular and intraperitoneal administration. Furthermore, this peptide was also effective when administered orally.
  • YVLSR activates central ⁇ receptors, and further activates ⁇ 1 , 5-HT 1A , D 1 , and GABA A receptors, and is considered to exhibit an anxiolytic action.
  • Benzodiazepines such as diazepam, known as common anxiolytic drugs, bind to the benzodiazepine binding site of the GABA A receptor and show anxiolytic activity, whereas YVLSR does not show affinity for this binding site Therefore, it is considered that GABA release is promoted and an anxiolytic action is exhibited. Therefore, it was found that the pathway is different from that of conventional anxiolytic drugs.
  • the anti-anxiety drug of the present invention may have a different mechanism of action from conventional anxiolytic drugs, and can provide a new type of drug.
  • drugs that have a mental stress relieving action often have a sleep-inducing action, and a typical anxiolytic drug diazepam is prescribed as a sleep inducer.
  • YVLSR has also been shown to activate GABA A receptors that mediate sleep-induced effects. Therefore, the pharmaceutical composition of the present invention can also be used for sleep induction and sleep improvement.
  • the present inventors have found a plurality of anxiolytic peptides derived from milk protein.
  • SEQ ID NO: 1 is a designed peptide.

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Abstract

L'invention concerne une composition pharmaceutique, qui contient un peptide qui est représenté par YVLSR, ou un analogue de celui-ci, comme ingrédient actif.
PCT/JP2011/061965 2010-05-26 2011-05-25 Composition pharmaceutique contenant un peptide biologiquement actif WO2011148972A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018164019A1 (fr) * 2017-03-04 2018-09-13 Kyoto University Peptides thérapeutiques

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03220131A (ja) * 1990-01-23 1991-09-27 Snow Brand Milk Prod Co Ltd カソキシンｃを有効成分とする血圧降下剤
JP2002080495A (ja) * 2000-09-04 2002-03-19 Univ Kyoto 新規な血清コレステロール低下ペプチド
JP2009013143A (ja) * 2007-07-09 2009-01-22 Nisshin Pharma Inc 睡眠改善用組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03220131A (ja) * 1990-01-23 1991-09-27 Snow Brand Milk Prod Co Ltd カソキシンｃを有効成分とする血圧降下剤
JP2002080495A (ja) * 2000-09-04 2002-03-19 Univ Kyoto 新規な血清コレステロール低下ペプチド
JP2009013143A (ja) * 2007-07-09 2009-01-22 Nisshin Pharma Inc 睡眠改善用組成物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHIHIRO SUZUKI ET AL.: "Hotai C3a Agonist Peptide WPLPR no Ko Fuan Sayo Oyobi sono Sayo Kiko", THE JAPANESE SOCIETY OF NUTRITION AND FOOD SCIENCE TAIKAI KOEN YOSHISHU, vol. 63RD, 2009, pages 200 *
SUZUKI C. ET AL.: "[Trp5] -ORYZATENSIN(5-9), AN AGONIST PEPTIDE FOR COMPLEMENT C3a RECEPTOR, EXHIBITS ANXIOLYTIC-LIKE EFFECT MEDIATED BY PROSTAGLANDIN E2", PEPTIDE TORONKAI KOEN YOSHISHU, vol. 46TH, 2009, pages 106 *
SUZUKI C. ET AL.: "[Trp5]-oryzatensin (5-9), an Agonist Peptide for Complement C3a Receptor, Exhibits Anxiolytic-Like Effect Mediated by Prostaglandin E2", PEPTIDE SCIENCE, vol. 2009, March 2010 (2010-03-01), pages 269 - 272 *
TAKAHASHI M. ET AL.: "Identification of casoxin C, an ileum-contracting peptide derived from bovine kappa-casein, as an agonist for C3a receptors.", PEPTIDES, vol. 18, no. 3, 1997, pages 329 - 336 *
YOSHIKAWA M. ET AL.: "Complement C3a Agonist Peptides Derived from Food Proteins.", PEPTIDE CHEMISTRY, vol. 1995, 1996, pages 413 - 416 *
YOSHIKAWA M. ET AL.: "Orally active memory- enhancing peptides obtained by designing bioactive peptides derived from food proteins.", PEPTIDE SCIENCE, vol. 1997, 1999, pages 728 - 730 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018164019A1 (fr) * 2017-03-04 2018-09-13 Kyoto University Peptides thérapeutiques

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