TW201716080A - Composition for stimulating trpv1 - Google Patents

Abstract

Provided are a composition for stimulating TRPV1, a use for the composition for stimulating TRPV1, and a method for stimulating TRPV1. It was discovered that a specific cyclic dipeptide or a salt thereof has a TRPV1 stimulation effect. The present invention provides an effective and novel means that contributes to the enhancement of various physiological activities such as the acceleration of energy consumption.

Description

TRPV1 stimulation composition

The present invention relates to a TRPV1 stimulating composition. More specifically, the present invention relates to a TRPV1 stimulating composition containing a cyclic dipeptide or a salt thereof as an active ingredient, a use of a cyclic dipeptide for stimulating TRPV1 or a salt thereof, and a method of stimulating TRPV1.

TRPV1 (Transient Receptor Potential Cation Channel, subfamily V, member 1) is a molecule belonging to the TRP (transient receptor potential) ion channel superfamily, which is known as a receptor for the recognition of nociception such as pain or hot feeling. TRPV1 is expressed in the sensory nerve or brain, and is depolarized with cation inflow due to stimulation of TRPV1 at the end of the sensory nerve, and is received as a noxious stimulus. Examples of the agonist of TRPV1 include capsaicin (non-patent document 1) and capsailate (non-patent document 2); pepper base (non-patent document 3); ginger Ginger oil and gingerol, which are spicy ingredients, were confirmed to be activated by heat (threshold: 43 ° C) or protons.

As a biological effect of TRPV1 stimulation, promotion energy can be cited The amount of consumption. For example, in Non-Patent Document 4, it was confirmed that the energy consumption of the capsaicin ester of the TRPV1 stimulating agent was increased after long-term administration to normal mice; and the body heat generation analysis was performed as a normal mouse and a TRPV1 knockout mouse. As a result, it was confirmed that the increase in energy consumption due to the administration of capsaicin esters was through TRPV1 in the digestive tract.

Further, regarding TRPV1 stimulation, in Non-Patent Document 5, normal mice and TRPV1 knockout mice were used to investigate the effect of capsaicin esters on suppressing body weight gain and inhibiting visceral fat accumulation, since only in normal mice. This effect was observed, and thus it was confirmed that the inhibition of weight gain of capsaicin esters and the inhibition of body fat accumulation were stimulated by TRPV1.

Further, it has been reported that TRPV1 stimulation also affects muscle or optic nerve disorders. For example, according to Patent Document 1, the intracellular calcium concentration is controlled by TRPV1, which is important for the activation of the protein synthesis pathway by mTOR and the subsequent muscle hypertrophy, and shows that muscle stimulation can be promoted and alleviated by TRPV1 stimulation. The possibility of muscle atrophy. Further, according to Patent Document 2, it is suggested that the TRPV1-specific agonist is a prophylactic or therapeutic agent for use as an optic nerve disorder, particularly an optic nerve disorder or glaucomatous stenosis caused by glaucoma.

In addition to the above agonist, a polyphenol analog or a hop water extract (Patent Document 3) and an inhibitory cysteine structure (ICK) vanillotoxin (Patent Document 4) may be mentioned. Wait.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2013/141202

[Patent Document 2] Japanese Patent Laid-Open Publication No. 2010-24219

[Patent Document 3] Japanese Patent Laid-Open Publication No. 2014-117239

[Patent Document 4] Japanese Patent Application Publication No. 2010-510227

[Non-patent literature]

[Non-Patent Document 1] Nature 389: 816, 1997

[Non-Patent Document 2] Neuropharmacol. 44: 958, 2003

[Non-Patent Document 3] Br. J. Pharmacol. 144: 781, 2005

[Non-Patent Document 4] Non-pungent capsinoids increased metabolic rate and promoted fat oxidation via the gastrointestinal TRPV1 in mice, F. Kawabata et al.

[Non-Patent Document 5] Ajinomoto Co., Ltd. "There is research information for health" (http://www.ajinomoto.com/jp/presscenter/press/detail/2009_11_02.html)

An object of the present invention is to provide a composition for TRPV1 stimulation. Further, an object of the present invention is to provide a method for stimulating the use of TRPV1 and a method of stimulating TRPV1.

As a result of intensive studies on the above-mentioned problems, the present inventors have found that a specific cyclic dipeptide or a salt thereof has a remarkable TRPV1 stimulating effect. Based on this finding, the inventors of the present invention have completed the present invention.

That is, the present invention relates to the following, but is not limited thereto.

(1) A TRPV1 stimulating composition comprising a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, wherein the cyclic dipeptide or a salt thereof is contained Select cyclohexane aspartame [Cyclo(Asp-Phe)], cyclohistamine Cyclo(His-Phe), cycloalkane leucine (Cyclo (Leu-Trp)], ring Cyclo(Gly-Trp), Cyclo(Phe-Trp), Cyclo(Ser-Tyr), Cyclosamine 醯Glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine proline [Cyclo(Met-Pro)], cyclic amidoxime tyrosine [Cyclo(Pro-Tyr)], cyclosamine serotonin [Cyclo(Ser-Ser)], cyclopropylamine lysine [Cyclo(Ala-Pro)], cyclic amidoxime quinine [Cyclo( Pro-Val)], cyclopropylamine lysine [Cyclo(Ala-Ser)], cyclomethamine sulphate [Cyclo(Pro-Thr)], and cycloaspartame glycine [Cyclo(Asp) -Gly)] One or more of the groups formed.

(2) The TRPV1 stimulating composition according to (1), which is intended to promote energy expenditure, promote body heat generation, promote metabolism, inhibit weight gain, inhibit visceral fat accumulation, increase muscle mass, reduce muscle atrophy, or prevent or treat optic nerve Use of obstacles.

(3) The TRPV1 stimulating composition according to (1) or (2), wherein the cyclic dipeptide or a salt thereof is obtained from a peptide derived from an automatic plant.

(4) The TRPV1 stimulating composition according to any one of (1) to (3), which is accompanied by an indication of a function exerted by TRPV1 stimulation.

(5) The TRPV1 stimulating composition according to (4), wherein the function is marked by "prevention of obesity", "improvement of obesity", "increase in weight gain", "inhibition of accumulation of body fat", "inhibition of internal organs" "Accumulation of fat", "enhanced energy consumption", "improving body heat generation", "promoting metabolism", "enhancing muscle strength", "suppressing muscle strength reduction", "improving optic nerve disorder", and "preventing optic nerve disorder" Group of people.

The TRPV1 stimulating composition according to any one of (1) to (5) wherein the composition is a pharmaceutical agent.

(7) A cyclic dipeptide or a salt thereof comprising an amino acid as a constituent unit, which is for use in stimulating TRPV1, and the cyclic dipeptide or a salt thereof is selected from the group consisting of cyclo-aspartame and phenylalanine [Cyclo(Asp-Phe)], cyclohistamine Cyclo(His-Phe), cycloalkonium leucine (Cyclo (Leu-Trp)], cycloglycine leucine Gly-Trp)], Cyclomethamine (Cyclo-Prp), Cyclo(Ser-Tyr), Cycloamine (Cyclo-Glu-Glu) )], cyclopropylamine alanine [Cyclo(Ala-Ala)], Cyclomethionine [Cyclo(Met-Pro)], Cyclomethamine [Cyclo(Pro-Tyr)], Cyclo(Ser-Ser), Ring Amphetamine [Cyclo(Ala-Pro)], Cyclomethamine [Cyclo(Pro-Val)], Cyclopropylamine (Cyclo [Ala-Ser]], Cyclohexylamine One or two or more of the group consisting of Cyclo (Pro-Thr) and Cyclo (Asp-Gly).

(8) A method for stimulating TRPV1 using a cyclic dipeptide or a salt thereof having an amino acid as a constituent unit as an active ingredient, and the cyclic dipeptide or a salt thereof is selected from the group consisting of cycloaspartame Cyclopropylamino acid [Cyclo(Asp-Phe)], cyclohistamine Cyclo(His-Phe), cycloamine leucine (Cyclo (Leu-Trp)], cycloglycine leucine Cyclo(Gly-Trp)], Cycloprine (Phe-Trp), Cyclo(Ser-Tyr), Cycloamine (Cyclo) -Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine proline [Cyclo(Met-Pro)], cyclodecylamine tyrosine [Cyclo(Pro-Tyr) ], Cyclo (Ser-Ser), Cyclo (Ala-Pro), Cyclo (Pro-Val), ring Cyclo(Ala-Ser), Cyclo(Pro-Thr), and Cyclo(Asp-Gly) One or more of the group.

According to the present invention, a composition having an excellent TRPV1 stimulating effect can be provided. By using the present invention in any method of administration The TRPV1 stimulation composition can provide an effect of promoting energy expenditure, promoting body heat generation, promoting metabolism, inhibiting weight gain, and suppressing accumulation of visceral fat by TRPV1 stimulation. In addition, when the TRPV1 stimulating composition of the present invention is used, it is expected to exhibit various physiological effects such as a muscle activity and an inhibitor of optic nerve disorder which have been reported to be stimulated by TRPV1.

1.TRPV1 and TRPV1 stimulation

In the present specification, "TRPV1" means a molecule which is related to the identification of the nociception in the living body and which is specified by the name of Transient Receptor Potential Cation Channel, subfamily V, member 1. TRPV1 is a molecule belonging to the TRP ion channel superfamily, which is distinguished from other molecules of the same family (TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, TRPA1).

In the present specification, "TRPV1 stimulation" means activation of TRPV1 by stimulation. By activating TRPV1, various physiological effects can be caused. When TRPV1 is activated, it becomes a cation-passible, so it can be used to evaluate TRPV1 stimulation. For example, cells expressing TRPV1 can be used for evaluation by measuring changes in intracellular calcium ion concentration when a test substance is added thereto. In general, when a change in concentration is observed (particularly when an increase in intracellular calcium ion concentration is observed), it can be judged that TRPV1 is stimulated. Also, the degree of TRPV1 stimulation (strong or weak), For example, capsaicin or the like which uses an agonist can be used as a control group, and its relative value or the like can be used for evaluation.

2. Cyclic dipeptide

In the present specification, the term "cyclic dipeptide" refers to a cyclic two having a diketopiperazine structure which is characterized in that an amino acid is a constituent unit and is dehydrated and condensed by an amine group of an amino acid and a carboxyl group. Peptide. Therefore, the cyclic dipeptide is distinguished from the chain dipeptide. In the present specification, the cyclic dipeptide or a salt thereof is simply referred to as a cyclic dipeptide. Further, in the present specification, if the amino acid of the cyclic dipeptide is configured to be the same, the order of the above descriptions may be the first, for example, [Cyclo(Met-Arg)] and [Cyclo(Arg-Met). ] is the same as the cyclic dipeptide.

In the cyclic dipeptide, the terminal portion of the two amino acids is bonded through a guanamine bond (that is, a cyclic dipeptide having a ring formed by an amine terminal and a carboxy terminal bonded by a guanamine bond). a structure, and thus has a linear dipeptide (especially a linear dipeptide composed of the same amino acid) which is exposed to a polar group at a terminal portion of the molecule, and is cyclic The dipeptide is characterized by high fat solubility. Therefore, the cyclic dipeptide is superior in digestive tract permeability or membrane permeability to the linear dipeptide. This is also evident from the results of the previously reported compound penetration test using the rat to reverse the intestine (J. Pharmacol, 1998, 50: 167-172). Further, the cyclic dipeptide is considered to have improved resistance to various peptide enzymes due to its specific structure.

a cyclic dipeptide contained as an active ingredient in the present invention or The salt thereof is selected from the group consisting of Cyclo (Asp-Phe), Cyclo (His-Phe), and Cyclo (Leu-Trp). )], Cyclo(Gly-Trp), Cyclo(Phe-Trp), Cyclo(Ser-Tyr), Cycloglycine, Cyclo(Glu-Glu), Cyclo(Ala-Ala), Cyclomethamine, Cyclo(Met-Pro), Cyclodecylamine Cyclo(Pro-Tyr), Cyclo(Ser-Ser), Cyclo(Ala-Pro), Cycloamidamine Acid [Cyclo(Pro-Val)], cyclopropylamine dextran acid [Cyclo(Ala-Ser)], cyclomethamine sulphate [Cyclo(Pro-Thr)], and cycloaspartame glycine One or more of the groups formed by [Cyclo(Asp-Gly)]. The number of the cyclic dipeptides or the salts thereof is not particularly limited. However, in the present invention, it is preferred to use three or more selected from the above cyclic dipeptides or salts thereof as an active ingredient. Further, among the cyclic dipeptides or salts thereof, it is particularly preferred to be selected from the group consisting of cyclophosphamide (Cyclo (Gly-Trp)], cyclohistamine Cyclo (His-Phe), and ring white. A group of Cyclo(Leu-Trp), Cyclo(Asp-Phe), and Cyclo(Ser-Tyr) 1 or more; more preferably selected from the group consisting of Cyclo(Gly-Trp), Cyclo(His-Phe), and cycline One or more of the group consisting of Cyclo (Leu-Trp).

In the present specification, the "salt of a cyclic dipeptide" refers to any pharmacologically acceptable salt of the above cyclic dipeptide (including inorganic salts and organic salts). The salt), for example, may be mentioned as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an ammonium salt, a hydrochloride, a sulfate, a nitrate, a phosphate, an organic acid salt (acetate, citric acid) of the above cyclic dipeptide. Salt, maleate, malate, oxalate, lactate, succinate, fumarate, propionate, formate, benzoate, picrate, besylate, trifluoro Acetate or the like), but is not limited thereto. Salts of cyclic dipeptides can be readily formulated by any of the methods well known in the art by any method known in the art.

The cyclic dipeptide used in the present invention can be formulated in accordance with a method known in the art. For example, it can be produced by a chemical synthesis method, an enzyme method, or a microbial fermentation method, and can be synthesized by dehydrating and cyclizing a linear peptide, or according to Japanese Patent Laid-Open Publication No. 2003-252896 or Journal of Peptide Science. , 10, 737-737, 2004 describes the method of preparation. For example, an auto-plant peptide obtained by subjecting a raw material containing a protein of an automatic plant to an enzyme treatment or heat treatment is further subjected to high-temperature heat treatment to obtain a heat-treating substance of an auto-plant which is rich in a cyclic dipeptide. . From such a viewpoint, the cyclic dipeptide or a salt thereof used in the present invention may be a chemical or biosynthetic or may be obtained from a peptide derived from an automated plant.

3. To autopilot peptides

In the present specification, "the peptide of the automatic plant" is not particularly limited, and for example, soybean peptide, tea peptide, malt peptide, lactopeptide, placenta peptide, collagen peptide, and the like can be used. Among these, in the present invention, a collagen peptide and a soybean peptide are preferred. To autopilot peptides, can be used by A manufacturer of a raw material for protein or protein of an automatic plant or a commercially available product may be used.

3-1. Soybean peptide

The term "soybean peptide" as used in the present specification refers to a low molecular peptide obtained by subjecting soy protein to an enzyme treatment or heat treatment to lower the molecular weight of the protein. The soybean (scientific name: Glycine max) which is a raw material can be used without restricting the variety or the production place, and the processed product stage such as a pulverized product can also be used.

3-2. Tea peptide

The term "tea-winning peptide" as used in the present specification refers to a low-molecular peptide derived from tea obtained by subjecting a tea (including tea leaves or tea residue) extract to an enzyme treatment or heat treatment to lower the molecular weight of the protein. As the tea leaves for extracting raw materials, it is possible to extract a portion which can be drunk by using leaves, stems, and the like of tea leaves produced by tea tree (scientific name: Camellia sinensis). Further, the form is not limited to large leaves, powders, and the like. Regarding the harvest period of the tea, it can also be appropriately selected in accordance with the desired flavor.

3-3. Malt peptide

The term "malt peptide" as used in the present specification refers to a low molecular weight derived from malt obtained by subjecting an extract obtained from malt or a pulverized material thereof to an enzyme treatment or heat treatment to lower the molecular weight of the protein. Peptide. As a raw material, the malt peptide can be used without limiting the variety or origin, but it is particularly suitable. Use barley malt that germinates barley seeds. Further, in the present specification, barley malt is also simply expressed as malt.

3-4. Milk peptide

The term "milk peptide" as used in the present specification refers to a molecule which decomposes milk protein of a natural component derived from milk into a molecule having at least a plurality of amino acids bonded thereto. More specifically, a milk protein such as whey (whey protein) or casein is hydrolyzed by an enzyme such as protease, and the filtrate obtained by filtering is sterilized and/or concentrated and dried. Whey peptide, casein peptide, and the like.

3-5. Placenta peptide

Placenta refers to a placenta of mammals, which has been used as a health food, cosmetics, and pharmaceutical materials in recent years due to its excellent functionality. In the present specification, "placental peptide" refers to a placebo that is solubilized and submolecularized by enzyme treatment or subcritical treatment. Further, although it is different from the original meaning, the extract obtained from the placenta of the plant is used as a health food, a cosmetic, etc. as a physiological effect equivalent to the placenta from the placenta, and these are called plants. placenta. In the present specification, the "placental peptide" also includes a method of performing enzyme treatment or subcritical treatment on a plant placenta, and solubilizing and lowering the molecule.

3-6. Collagen peptide

"Collagen peptide" as used in this specification refers to collagen The protein or its pulverized material is subjected to an enzyme treatment or heat treatment to lower the molecular weight of the collagen to obtain a low molecular peptide. Collagen is the main protein of the connective tissue of animals, which is the largest amount of protein contained in the mammalian body of humans.

4. To auto-plant peptide heat treatment

As described above, by heat-treating the peptide of the auto plant in the future, it is possible to obtain a heat-treated peptide of an auto-plant which is rich in a cyclic dipeptide. In the present specification, "high-temperature heat treatment" means treatment at a temperature of 100 ° C or more and a pressure exceeding atmospheric pressure for a certain period of time. As the high-temperature high-pressure treatment apparatus, a pressure-resistant extraction apparatus, a pressure cooker, a hot press, or the like can be used in accordance with the conditions.

The temperature of the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or more, and is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, still more preferably 120 ° C to 140 ° C. Further, when a pressure-resistant extraction device is used as the heating device, the temperature indicates the value of the outlet temperature of the extraction column, and when the autoclave is used as the heating device, the temperature indicates the center temperature in the pressure vessel. The value of the temperature.

The pressure of the high-temperature heat treatment is not particularly limited as long as it is a pressure exceeding atmospheric pressure, and is preferably 0.101 MPa to 0.79 MPa, more preferably 0.101 MPa to 0.60 MPa, and still more preferably 0.101 MPa to 0.48 MPa.

The high-temperature heat treatment time is not particularly limited as long as a treatment containing a cyclic dipeptide is obtained, and is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably 60 minutes to 300 minutes. Minutes.

In addition, the high-temperature heat treatment conditions of the peptide of the automatic plant are not particularly limited as long as the treatment product containing the cyclic dipeptide is obtained, and it is preferable that [temperature: pressure: time] is [100 ° C to 170 ° C: 0.101 MPa. ~0.79MPa: 15 minutes to 600 minutes], more preferably [110°C~150°C: 0.101MPa~0.60MPa: 30 minutes to 500 minutes], and more preferably [120°C~140°C: 0.101MPa~0.48MPa) : 60 minutes to 300 points].

Further, the obtained heat-treating substance of the peptide of the automatic plant may be subjected to filtration, centrifugation, concentration, ultrafiltration, freeze-drying, powdering or the like as desired. Further, if the specific cyclic dipeptide in the heat treatment of the peptide of the auto-plant is not satisfying the desired content, other peptides derived from automatic plants or commercially available products or synthetic products may be used for the specific cyclic dipeptide which is insufficient. Appropriate addition.

5.TRPV1 stimulation composition

5-1. TRPV1 stimulating composition containing a cyclic dipeptide

One aspect of the present invention is a TRPV1 stimulating composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient.

The TRPV1 stimulating composition of the present invention contains a compound selected from the group consisting of Cyclo (Asp-Phe), Cyclo (His-Phe), and Cyclosamine. Acid [Cyclo(Leu-Trp)], cycloglycine serotonin [Cyclo(Gly-Trp)], Cyclomethamine Cyclosamine (Cyclo-Prp), Cyclosamine tyrosine [Cyclo (Ser-Tyr)], cyclophosphamide glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine valinate [Cyclo(Met-) Pro)], Cyclo (Pro-Tyr), Cyclo (Ser-Ser), Cyclo (Ala-Pro) , Cyclo(Pro-Val), Cyclo(Ala-Ser), Cyclo(Pro-Thr), and ring One or two or more cyclic dipeptides or salts thereof of the group consisting of Cyclo (Asp-Gly) are used as active ingredients. The number of the cyclic dipeptide or the salt thereof contained in the TRPV1 stimulating composition of the present invention is not particularly limited, but in the present invention, it is preferred to contain three or more selected from the above cyclic dipeptide or a salt thereof. . Among the above cyclic dipeptides or salts thereof, it is particularly preferred to be selected from the group consisting of Cyclo(Gly-Trp), cyclo-His-Phe, and cycloamine. 1 of the group consisting of Cyclo (Leu-Trp), Cyclo(Asp-Phe), and Cyclo(Ser-Tyr) Or more than 2; more preferably selected from the group consisting of Cyclo (Gly-Trp), Cyclo (His-Phe), and cyclidine leucine One or two or more of the groups formed by [Cyclo (Leu-Trp)].

The content of the cyclic dipeptide or the salt thereof in the TRPV1 stimulating composition of the present invention may be any amount as long as the desired effect of the present invention is obtained in consideration of the administration form, the administration method, and the like. limited. For example, when a soybean peptide, a tea peptide, a malt peptide, a lactopeptide, a placenta peptide, or a collagen peptide is used as a raw material, the content of the cyclic dipeptide or a salt thereof in the composition of the present invention is The total amount is 200 ppm/Brix or more, preferably 300 ppm/Brix or more, and is 5000 ppm/Brix or less, preferably 4000 ppm/Brix or less, and typically 200 to 5000 ppm/Brix, It is preferably 300 to 4000 ppm/Brix. Further, in the composition for stimulating TRPV1 of the present invention, Cyclo(Asp-Phe), Cyclo(His-Phe), cycloamine leucine [Cyclo(Leu-Trp)], cycloglycine tryptophanic acid [Cyclo(Gly-Trp)], cyclomethacrylic acid tryptophanic acid [Cyclo(Phe-Trp)], cyclosamine tyrosine acid [Cyclo ( Ser-Tyr)], cyclophosphamide glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine valinate [Cyclo (Met-Pro) )], Cyclo (Pro-Tyr), Cyclo (Ser-Ser), Cyclo (Ala-Pro), Cyclo(Pro-Val), Cyclo(Ala-Ser), Cyclo(Pro-Thr), Cyclosporin The content of the Cyclo(Asp-Gly) or the salt corresponding thereto is 1.0 ppm/Brix or more, preferably 3.0 ppm/Brix or more, and is 3000 ppm/Brix or less, preferably 2000 ppm. Below /Brix, typically, it is 1.0 to 3000 ppm/Brix, preferably 3.0 to 2000 ppm/Brix. In the present invention, the content of the cyclic dipeptide or a salt thereof is expressed by the amount per unit of Brix (Bx) as described above. In the present specification, the "amount per unit of Brix" means an amount specified by a mass percentage of a sucrose solution (aqueous solution containing only sucrose as a solute) corresponding to 20 °C. Further, unless otherwise specified, "ppm" as used in the specification means ppm by weight/capacity (w/v), and when the specific gravity of 1.0 ppm/Brix solvent is 1, it is converted to 0.1 mg/mL. It is 0.01% by weight.

The content of the cyclic dipeptide or a salt thereof can be in accordance with a known method Determination. For example, it can be determined using an LC-MS/MS or a sugar meter.

Further, the TRPV1 stimulating composition of the present invention may be a heat-treating substance containing a peptide of an automatic plant as an active ingredient, and the heat-treating substance of the peptide of the automatic plant contains one or both of the cyclic dipeptides or salts thereof. the above. The heat treatment product of the peptide of the automatic plant is not particularly limited, and is preferably a heat treatment product of soybean peptide and heat treatment of collagen peptide.

When the heat-treating substance of the peptide of the present invention is used, the content of the TRPV1 stimulating composition of the present invention can be obtained by considering the administration form, the administration method, and the like, and the desired effect of the present invention can be obtained. There are no special restrictions. For example, the content is 0.001% by weight or more, preferably 0.01% by weight or more, and more preferably 0.1% by weight or more based on the total weight of the composition of the present invention. Further, the content of the peptide heat-treated product of the automatic plant is 99% by weight or less, preferably 50% by weight or less, and more preferably 10% by weight or less based on the total weight of the composition of the present invention.

5-2. Other ingredients

The TRPV1 stimulating composition of the present invention may contain any additives or any components which are usually used in addition to the above-mentioned active ingredients in accordance with the form. Examples of such additives and/or components include physiologically active ingredients such as vitamins and vitamins such as vitamin E and vitamin C, minerals, nutrients, and flavors, and examples thereof include excipients blended at the time of formulation. Binder, emulsifier, stretcher (isotonic), buffer, dissolution aid, preservative, stabilizer, antioxidant, colorant, coagulant, or coating Agents, etc., but are not limited thereto.

5-3. Use

The TRPV1 stimulating composition of the present invention is characterized in that it contains the above-mentioned active ingredient, which stimulates TRPV1 to cause various physiological effects. In the present invention, by stimulating TRPV1 to activate it, it can be applied to promote energy consumption, promote body heat generation, promote metabolism, inhibit weight gain, inhibit visceral fat accumulation, increase muscle mass, and reduce muscle atrophy, and can be effectively performed. Prevention or treatment of optic nerve disorders. Therefore, the composition of the present invention is a composition for promoting energy consumption, promoting body heat generation, promoting metabolism, inhibiting weight gain, inhibiting visceral fat accumulation, increasing muscles, reducing muscle atrophy, or preventing or treating optic nerve disorders. Composition for TRPV1 stimulation for treatment. The composition for stimulating TRPV1 of the present invention can also be used as a composition for promoting energy expenditure, a composition for promoting body heat generation, a composition for promoting metabolism, a composition for suppressing body weight gain, and for suppressing accumulation of visceral fat. A composition for preventing or treating a composition, a composition for increasing muscles, a composition for reducing muscle atrophy, or an optic nerve disorder. In addition, in this specification, "prevention" and "treatment" include the concept of making the current state better and preventing the state which is worse than the current state, so improvement, restoration, mitigation, relaxation, etc. The terminology can also be included in this.

The TRPV1 stimulating composition of the present invention can be used, for example, in the form of a tablet, a granule, a powder, a powder, a capsule, or the like, or a general liquid, according to a known method. A liquid preparation such as a suspending agent or an emulsion. These compositions can be taken directly with water or the like. Further, it can be formulated into a form which can be easily blended (for example, a powder form or a particle form), and is used, for example, as a raw material of a pharmaceutical.

The TRPV1 stimulation composition of the present invention can be provided in the form of a drug as an example, but is not limited to the present embodiment. The agent may be provided directly in the form of a composition or may also be in the form of a composition of the agent. The composition of the present invention may, for example, be a pharmaceutical composition, a food or beverage composition, a food composition, a beverage composition, a cosmetic composition or the like, but is not limited thereto. Non-limiting examples of the food composition include functional foods, health supplement foods, nutritional functional foods, special purpose foods, specific health foods, nutritional supplement foods, food therapy foods, health foods, and supplements. , food additives, etc.

The TRPV1 stimulating composition of the present invention can be applied for therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it may be exemplified as a pharmaceutical product, a pharmaceutical product, a cosmetic, or the like, or a pharmaceutical law, but it is expressly or implicitly applied to promote energy consumption, promote body heat generation, and promote metabolism. The use of a composition that inhibits weight gain, inhibits visceral fat accumulation, increases muscle mass, reduces muscle atrophy, or prevents or treats optic nerve disorders.

In another aspect of the present invention, the composition for TRPV1 stimulation having a function of stimulating by TRPV1 is used. Such a label or a functional label is not particularly limited, and examples thereof include "prevention of obesity", "improvement of obesity", "increase in weight gain", "inhibition of accumulation of body fat", "inhibition of accumulation of visceral fat", and "High energy consumption", "improving body heat generation", "promoting metabolism", "preventing obesity", "improving obesity", "enhancing muscle strength", "suppressing muscle strength", "improving optic nerve disorder", "preventing optic nerve disorder" The records in the same meaning as these are also included in the label. In this specification, the label as indicated by the label and the functional label may be attached to the composition itself or to the container or package of the composition.

The TRPV1 stimulating composition of the present invention can be ingested in an appropriate manner depending on the form. The method of ingestion is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can be moved in circulating blood. For example, it may be an oral solid preparation such as a tablet, a coated tablet, a granule, a powder, or a capsule; an oral liquid preparation such as an internal liquid or a syrup; an injection, an external preparation, a suppository, Or a form of a non-oral preparation such as a percutaneous absorption agent, but is not limited thereto. In addition, in this specification, "ingestion" is used as a whole aspect including ingestion, administration, or drinking.

The applicable amount of the TRPV1 stimulating composition of the present invention is appropriately set depending on the form, the administration method, the purpose of use, and the age, body weight, and symptoms of the patient or the diseased subject to be administered, and is not necessarily constant. The effective human intake of the composition of the present invention is not constant. For example, the human body having a body weight of 50 kg per day, preferably 10 mg or more, more preferably 100 mg, based on the total amount of the cyclic dipeptide or its salt of the active ingredient thereof. the above. Further, the administration may be performed in a single or divided number of times within one day within the range of the desired amount of administration. The period of investment is also arbitrary. In addition, the effective human intake of the composition of the present invention refers to the intake amount of the TRPV1 stimulating composition of the present invention which exhibits an effective effect in humans.

The TRPV1 stimulating composition of the present invention is preferably a human, but may be a livestock animal such as a cow, a horse or a goat; a pet animal such as a dog, a cat or a rabbit, or a mouse, a rat, a guinea pig, or the like. Experimental animals such as monkeys. When administered to animals other than humans, the amount of use per mouse per day for about 20 g per mouse is also dependent on the content of the active ingredient in the composition, the state of the subject, body weight, sex, and The amount of the cyclic dipeptide or a salt thereof is preferably in an amount of preferably 10 mg/kg or more, more preferably 100 mg/kg or more, based on the total amount of the cyclic dipeptide or a salt thereof.

6. Use of a cyclic dipeptide or a salt thereof to stimulate TRPV1

In one aspect of the invention, a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit is used for stimulating TRPV1. Preferably, it is selected from the group consisting of Cyclo (Asp-Phe), Cyclo (His-Phe), and Cyclo (Leu-Trp). ], Cyclo(Gly-Trp), Cyclo(Phe-Trp), Cyclo(Ser-Tyr), Ring Glutenin glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine proline [Cyclo(Met-Pro)], cyclic amidoxime Cyclo(Pro-Tyr), Cyclo(Ser-Ser), Cyclo(Ala-Pro), Cycloamine Amidin [Cyclo(Pro-Val)], cyclopropylamine lysine [Cyclo(Ala-Ser)], cyclomethamine sulphate [Cyclo(Pro-Thr)], and cycloaspartame glycine [ One or more of the groups formed by Cyclo (Asp-Gly)] A cyclic dipeptide or a salt thereof is used for stimulating the use of TRPV1. More preferably, it is used for stimulating TRPV1 in which three or more selected from the above-mentioned cyclic dipeptide or its salt are contained.

The use of the present invention includes, for example, the aforementioned ring for promoting energy expenditure, promoting body heat generation, promoting metabolism, inhibiting weight gain, inhibiting visceral fat accumulation, increasing muscle, reducing muscle atrophy, or preventing or treating optic nerve disorders. The use of the dipeptide or a salt thereof is not limited thereto. Moreover, the use is for use in human or non-human animals and may be therapeutic for non-therapeutic use. Here, "non-therapeutic" means not including medical behavior, that is, does not include the concept of treatment of the human body caused by treatment.

7. Method of stimulating TRPV1

One aspect of the present invention is a method for stimulating TRPV1 using a specific cyclic dipeptide or a salt thereof having an amino acid as a constituent unit as an active ingredient. Preferably, the method comprises the use of: Cyclo (Asp-Phe), cyclo-His-Phe, Cyclo-His-Phe, Cyclo (His-Phe), Cyclo (Amino-Phe) Leu-Trp)], cycloglycine tryptophanic acid [Cyclo(Gly-Trp)], cyclomethacrylic acid tryptophan acid [Cyclo(Phe-Trp)], cyclosamine tyrosine acid [Cyclo(Ser-Tyr) )], cyclophosphamide glutamic acid [Cyclo (Glu-Glu)], cyclopropylamine acetaminolate [Cyclo (Ala-Ala)], cyclomethine valinate [Cyclo (Met-Pro)], Cyclo(Pro-Tyr), Cyclo(Ser-Ser), Cyclo(Ala-Pro), Cyclodecylamine Proline (Pro-Pro- Val)], Cyclo(Ala-Ser), Cyclo(Pro-Thr), and Cyclo(Asp-Gly) A method of stimulating TRPV1 by using one or two or more of the obtained cyclic dipeptides or salts thereof as an active ingredient. More preferably, it comprises a method of stimulating TRPV1 using three or more selected from the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient.

In another aspect of the method, the method for stimulating TRPV1 comprises administering a therapeutically effective amount to a target which is necessary for stimulation with TRPV1, using a specific cyclic dipeptide or a salt thereof as an active ingredient. Preferably, it is a method for stimulating TRPV1, which comprises a method selected from the group consisting of Cyclo(Asp-Phe), Cyclo(His-Phe), and cycloamine oxime Tryptophan acid [Cyclo(Leu-Trp)], cycloglycine tryptophanic acid [Cyclo(Gly-Trp)], cyclomethacrylic acid tryptophan acid [Cyclo(Phe-Trp)], cyclosamine tyrosine [Cyclo(Ser-Tyr)], cyclophosphamide glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine valinate [Cyclo( Met-Pro)], cyclomethamine tyrosine [Cyclo(Pro-Tyr)], cyclosamine serotonin [Cyclo (Ser-Ser)], cyclopropylamine proline [Cyclo (Ala-Pro) )], Cyclo (Pro-Val), Cyclo (Ala-Ser), Cyclo (Pro-Thr), And one or two or more of the cyclic dipeptides or salts thereof of the group consisting of Cyclo (Asp-Gly) are administered as therapeutically effective amounts. More preferably, it is a method of stimulating TRPV1, which comprises administering the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient, and administering the therapeutically effective one. the amount.

Among the above methods, the target of TRPV1 stimulation is the same as the above-mentioned application target of the TRPV1 stimulation composition of the present invention. In the present specification, the therapeutically effective amount means the amount by which TRPV1 is stimulated when the TRPV1 stimulating composition of the present invention is administered to the subject. The specific effective amount is appropriately set depending on the administration form, the administration method, the purpose of use, and the age, weight, symptoms, and the like of the subject, and is not necessarily limited.

In the method of the present invention, the specific cyclic dipeptide or a salt thereof can be administered as a form containing a specific cyclic dipeptide or a salt thereof as a therapeutically effective amount.

According to the method of the present invention, TRPV1 can be stimulated without causing side effects.

[Examples]

The invention is described in more detail below by way of examples, without thereby limiting the scope of the invention. It will be apparent to those skilled in the art that the present invention may be practiced with various modifications and changes.

Example 1. Stimulation of TRPV1 by cyclic dipeptide

These TRPV1 stimulating effects were evaluated using various cyclic dipeptide samples chemically synthesized. Specifically, CHO cells (Chinese hamster ovary cells) expressing human TRPV1 were suspended in DMEM (Invitrogen) containing 0.1% FBS, and seeded in a 384-well microplate at 3.5 × 10 ⁴ cells/90 μL/well. Next, 20 mM Hepes buffer (Invitrogen) (pH 7.4) containing a fluorescent probe (Calsium 4, Molecular Device) was added to each well, and the mixture was equilibrated at 37 ° C for 60 minutes and then at 22 ° C for 15 minutes. Thereafter, the analysis disk is placed in a microplate analyzer (CellLux, PerkinElmer), and the change in intracellular calcium ion concentration caused by the addition of the cyclic dipeptide solution or the reference agonist solution is measured by the fluorescence intensity ( Reaction rate). Further, the reference agonist solution was a capsaicin solution prepared to have a final concentration of 1 μM.

The TRPV1 stimulating effect of the cyclic dipeptide sample was calculated by adding the reference agonist solution to the intracellular calcium ion concentration (reaction rate) of 100%, and calculating the relative value (%) to add the cyclic two. The reaction rate at the time of the peptide sample was evaluated. The number of tests was set to n = 2, and the average value of the reaction rate when the cyclic dipeptide sample was added was determined. The results are shown in Table 1. Further, the concentrations in the tables are expressed as the final concentration of the cyclic dipeptide in the analysis system.

From the above results, it is apparent that the cyclic dipeptides shown in Table 1 all have a TRPV1 stimulating effect.

Example 2. Review of TRPV1 stimulation of heat treatment of collagen peptide and heat treatment of soybean peptide

(1) Preparation of heat treatment of collagen peptide

A heat treatment of collagen peptide was used as a collagen peptide heat treatment. The collagen peptide heat-treating product is produced by treating the collagen peptide in a liquid at a high temperature and pressure. Specifically, distilled water was added to a collagen peptide (HACP-50, manufactured by Jellice Co., Ltd.) at a concentration of 10 g/100 ml, and placed in a autoclave (manufactured by TOMY SEIKO Co., Ltd.) to apply 135. °C, 0.31MPa, 10 hours high temperature and high pressure treatment.

(2) Preparation of heat treatment of soybean peptide

The heat treatment of the soybean peptide was used as a heat treatment for the soybean peptide. The soybean peptide heat treatment is produced by treating the soybean peptide in a liquid at a high temperature and pressure. Specifically, 3 g of soy peptide (HINUTE AM, manufactured by Fuji Oil Co., Ltd.) was added, and about 15 ml of distilled water was added thereto, and placed in a autoclave (manufactured by TOMY SEIKO Co., Ltd.), and a high temperature of 135 ° C, 0.31 MPa, and 3 hours was applied. High pressure treatment.

(3) Evaluation of TRPV1 stimulation

These TRPV1 stimulating effects were evaluated using the collagen peptide heat-treated product prepared as described above and the lyophilized product of the heat treatment of the soybean peptide. Specifically, CHO cells (Chinese hamster ovary cells) expressing human TRPV1 were suspended in DMEM (Invitrogen) containing 0.1% FBS, and seeded in a 384-well microplate at 3.5 × 10 ⁴ cells/90 μL/well. Next, 20 mM Hepes buffer (Invitrogen) (pH 7.4) containing a fluorescent probe (Calsium 4, Molecular Device) was added to each well, and the mixture was equilibrated at 37 ° C for 60 minutes and then at 22 ° C for 15 minutes. Thereafter, the analysis disk was placed in a microplate analyzer (CellLux, PerkinElmer), and the collagen peptide heat-treated product which was reconstituted to make the final concentration in the analysis system 1.0 mg/mL or The variation of the intracellular calcium ion concentration (reaction rate) caused by the addition of the soybean peptide heat-treated product or the addition of the reference agonist solution. Further, the reference agonist solution was a capsaicin solution prepared to have a final concentration of 1 μM.

The TRPV1 stimulating effect of the heat treatment of the collagen peptide or the heat treatment of the soybean peptide is based on the change (reaction rate) of the intracellular calcium ion concentration when the reference agonist solution is added, and the relative value (%) The reaction rate at the time of adding the test material was calculated and evaluated. The number of tests was set to n=2, and the average value of the reaction rate when the test material was added was determined. The results are shown in Table 2.

From the above results, it is apparent that both the collagen peptide heat-treated product and the soybean peptide heat-treated product have a TRPV1 stimulating effect. It is considered that a cyclic dipeptide (for example, a cyclic dipeptide shown in Table 1) contained in various materials has a possibility of contributing to the TRPV1 stimulating effect of these materials as one of the factors.

[Industrial availability]

The present invention provides a TRPV1 stimulating composition comprising a specific cyclic dipeptide or a salt thereof as an active ingredient. The present invention provides a novel means for promoting enhancement of various physiological activities such as energy consumption, and thus has high industrial applicability.

Claims (8)

A TRPV1 stimulating composition comprising a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient TRPV1 stimulating composition, and the cyclic dipeptide or a salt thereof is selected from the group consisting of a ring Aspartame, Cyclo(Asp-Phe), cyclo-His-Phe, Cyclo(Leu-Trp), Cycloglycine Tryptophan acid [Cyclo(Gly-Trp)], Cyclomethamine, Cyclo(Phe-Trp), Cyclo(Ser-Tyr), Cyclosamine glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine valinate [Cyclo(Met-Pro)], cyclic amidoxime tyrosine [Cyclo ( Pro-Tyr)], cyclosamine serotonin [Cyclo(Ser-Ser)], cyclopropylamine lysine [Cyclo(Ala-Pro)], cycloamidamine lysine [Cyclo(Pro-Val) )], Cyclo(Ala-Ser), Cyclo(Pro-Thr), and Cyclo(Asp-Gly) One or two or more of the groups formed. The TRPV1 stimulating composition according to claim 1, which is used for promoting energy expenditure, promoting body heat generation, promoting metabolism, inhibiting weight gain, inhibiting visceral fat accumulation, increasing muscles, reducing muscle atrophy, or preventing or treating optic nerve disorders. use. The TRPV1 stimulating composition according to claim 1 or 2, wherein the cyclic dipeptide or a salt thereof is obtained from a peptide derived from an automatic plant. The TRPV1 stimulating composition according to any one of claims 1 to 3, which is accompanied by an indication of a function exerted by TRPV1 stimulation. The TRPV1 stimulating composition of claim 4, wherein the function is marked by "preventing obesity", "improving obesity", "increasing weight gain", "suppressing accumulation of body fat", and "suppressing accumulation of visceral fat". "Enhanced energy consumption", "improving body heat generation", "promoting metabolism", "enhancing muscle strength", "suppressing muscle strength reduction", "improving optic nerve disorder", and "preventing optic nerve disorder" . The TRPV1 stimulating composition according to any one of claims 1 to 5, wherein the composition is a medicament. A cyclic dipeptide or a salt thereof comprising an amino acid as a constituent unit, which is used for stimulating TRPV1, and the cyclic dipeptide or a salt thereof is selected from the group consisting of cyclo-aspartame phenylalanine [Cyclo ( Asp-Phe)], cyclohistamine [Cyclo(His-Phe)], cyclo-amine leucine (Cyclo (Leu-Trp)], cycloglycine leucine (Cyclo-Gly-Trp) )], Cyclo(Phe-Trp), Cyclo(Ser-Tyr), Cyclo(Glu-Glu), Cyclopropylamine acetaminolate [Cyclo(Ala-Ala)], cyclomethamine valeric acid [Cyclo(Met-Pro)], cyclodecylamine tyrosine [Cyclo(Pro-Tyr)], cyclosamine Cyclo(Ser-Ser), Cyclo(Ala-Pro), Cyclo(Pro-Val), Cyclopropylamine lysine [Cyclo(Ala-Ser)], cyclomethamine sulphate [Cyclo (Pro-Thr)], and cyclodextrose glucosamine [Cyclo (Asp-Gly)] 2 or more. A method for stimulating TRPV1 using a cyclic dipeptide or a salt thereof having an amino acid as a constituent unit as an active ingredient, and The cyclic dipeptide or a salt thereof is selected from the group consisting of Cyclo (Asp-Phe), Cyclo (His-Phe), and cycloamine smectin. Acid [Cyclo(Leu-Trp)], cycloglycine serotonin [Cyclo(Gly-Trp)], Cyclomethamine Cyclosamine (Cyclo-Prp), Cyclosamine tyrosine [Cyclo (Ser-Tyr)], cyclophosphamide glutamic acid [Cyclo(Glu-Glu)], cyclopropylamine alanine [Cyclo(Ala-Ala)], cyclomethamine valinate [Cyclo(Met-) Pro)], Cyclo (Pro-Tyr), Cyclo (Ser-Ser), Cyclo (Ala-Pro) , Cyclo(Pro-Val), Cyclo(Ala-Ser), Cyclo(Pro-Thr), and ring One or more of the groups of Cyclo (Asp-Gly).