TW201717987A - Melanine-concentrating hormone receptor antagonist composition - Google Patents

Abstract

Provided are a melanine-concentrating hormone receptor antagonist composition, a use for the composition for inhibiting the binding of melanine-concentrating hormone to a receptor therefor, and a method for inhibiting the binding of melanine-concentrating hormone to a receptor therefor. It was discovered that a specific cyclic dipeptide or a salt thereof has a melanine-concentrating hormone receptor antagonist effect. The present invention provides an effective and novel means that contributes to the enhancement of various physiological activities such as weight gain resistance.

Description

Melanin-concentrating hormone receptor antagonistic composition

The present invention relates to a composition for melanin-concentrating hormone receptor antagonist. More specifically, the present invention relates to a melanin-concentrating hormone receptor antagonist composition comprising a cyclic dipeptide or a salt thereof as an active ingredient, a cyclic dipeptide for blocking the binding of melanin-concentrating hormone to its receptor, or The use of its salts and methods of inhibiting the binding of melanin-concentrating hormones to its receptors.

Obesity is a symptom associated with an increase in the intake of a high-fat diet, and it is one of the major problems in modern society because it causes a high proportion of endocrine and metabolic abnormalities such as diabetes, hyperlipidemia, hypertension, and arteriosclerosis. The onset of obesity has so far involved the involvement of neuropeptide Y or Melanin Concentrating Hormone (MCH), but it now focuses on the involvement of melanin-concentrating hormones.

Melanin-concentrating hormone (MCH) is a cyclic neuropeptide composed of 19 amino acids, which is mainly expressed in the lower hypothalamus in mammals. The relationship between MCH and obesity is reported, for example, in Non-Patent Document 1, and it is reported that the phenotypic analysis of MCH-deficient mice is changed by the decrease in the intake of the mouse's diet. thin.

Further, in Patent Document 1, the preventive or therapeutic agent for obesity disclosed has an NPY receptor or MCH receptor antagonism, and has been shown to improve various eating disorders (especially the hyperactivity of the feeding center or the inhibition of the satiety center). The abnormal appetite is caused by the prevention of obesity or the improvement of obesity, or the prevention or treatment of diseases associated with obesity. Further, in this patent document, it is also known that the preventive or therapeutic agent for obesity is also prophylactic or therapeutic for excessive diet confirmed in various stress diseases.

Such a relationship between MCH and obesity is now attracting attention, and it is strongly desired to develop an effective agent for anti-obesity. Among them, it is considered that a drug having a small side effect is expected from the viewpoint of human ingestion, and further, it is desired that the convenience in formulation or the absorption in the body is excellent.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 4359027

[Non-patent literature]

[Non-Patent Document 1] Nature. 1998 Dec 17; 396 (6712): 670-4.

An object of the present invention is to provide a composition for melanin-concentrating hormone receptor antagonist. Further, an object of the present invention is to provide a composition for inhibiting the binding of melanin-concentrating hormone to its receptor, and a method for inhibiting the binding of melanin-concentrating hormone to its receptor.

The inventors of the present invention have found that a specific cyclic dipeptide or a salt thereof has a remarkable melanin-aggregating hormone receptor antagonistic activity based on the results of intensive studies on the above-mentioned subject. Based on this finding, the inventors have finally completed the present invention.

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

(1) A melanin-concentrating hormone receptor antagonist composition comprising a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, a melanin-concentrating hormone receptor antagonist composition, The above cyclic dipeptide or a salt thereof is selected from the group consisting of cyclosamine, arginyl leucine [Cyclo(Arg-Leu)], cycloglycidyl arginine, Cyclo(Gln-Arg), cycloamine oxime Amino acid [Cyclo(Leu-Lys)], cyclopropylamino lysine [Cyclo (Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo (Asp-Ser)], cyclized amine Cyclo(Lys-Tyr), cyclo arginyl aspartic acid [Cyclo(Arg-Asp)], cycloallinyl phenylalanine [Cyclo(Leu-Phe)], Cyclo(Gln-Ser), Cyclo(Lys-Phe), Cyclo-Glycolic Acid [Cyclo(Gln-) Leu)], cyclopropylamine Phenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], ring From Cyclo(Lys-Ser), Cyclo(Gly-Lys), and Cyclo(Ala-Val) One or two or more of the groups.

(2) The melanin-concentrating hormone receptor antagonist composition according to (1), which is used for the prevention or treatment of diseases related to obesity, diseases related to obesity, metabolic hyperactivity, improvement of eating disorders, or appetite suppression.

(3) The melanin-concentrating hormone receptor antagonist composition according to (1) or (2), wherein the cyclic dipeptide or a salt thereof is derived from a peptide of an automatic plant.

(4) The melanin-concentrating hormone receptor antagonist composition according to any one of (1) to (3), which is accompanied by a function of a function exerted by melanin-concentrating hormone receptor antagonism.

(5) The melanin-concentrating hormone receptor antagonist composition according to (4), wherein the function is marked by "prevention of obesity", "improvement of obesity", "inhibition of weight gain", "inhibition of accumulation of body fat", "Suppressing the accumulation of visceral fat", "increasing the amount of energy consumed by the body", "promoting the decomposition of body fat", "making it easy to consume fat", "promoting the burning of fat", "improving eating disorders", "suppressing" Choose from a group of appetites, "metabolism" and "inhibition of dietary intake".

(6) The melanin-concentrating hormone receptor antagonist composition according to any one of (1) to (5) wherein the composition is an agent.

(7) A cyclic dipeptide or a salt thereof comprising an amino acid as a constituent unit for blocking the binding of melanin-concentrating hormone to a melanin-concentrating hormone receptor The use thereof is characterized in that the cyclic dipeptide or a salt thereof comprises a compound selected from the group consisting of cyclo arginyl leucine [Cyclo(Arg-Leu)], cycloglycine thiol arginine [Cyclo (Gln-Arg)] ], cycloalkyrosine dehydrogenated acid [Cyclo (Leu-Lys)], cyclopropylamine decyl leucine [Cyclo (Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo (Asp-Ser) )], cyclohexyl tyrosine [Cyclo(Lys-Tyr)], cyclospermine decyl aspartic acid [Cyclo (Arg-Asp)], cycloalkonyl phenyl phenylalanine [Cyclo (Cyclo (Arg-Asp)] Leu-Phe)], cycloglycine thioglycolic acid [Cyclo(Gln-Ser)], cycloalkylaminophenylalanine [Cyclo(Lys-Phe)], cycloglyoxime decylamine Acid [Cyclo(Gln-Leu)], cyclopropylaminophenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclospermine thiol Tyrosine [Cyclo(Arg-Tyr)], cyclohexylamine sulphate [Cyclo(Lys-Ser)], cycloglycidyl phthalic acid [Cyclo(Gly-Lys)], and cyclopropylamine One or two or more of the group consisting of Cyclo(Ala-Val).

(8) A method of using a cyclic dipeptide having a constituent unit of an amino acid as a constituent unit or a salt thereof as an active ingredient, which inhibits binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor, and is characterized by the aforementioned ring The dipeptide or a salt thereof is selected from the group consisting of cyclosamine, arginyl leucine [Cyclo(Arg-Leu)], cycloglutamine arginine, Cyclo(Gln-Arg), cycloamine amide Acid [Cyclo(Leu-Lys)], cyclopropylamino lysine [Cyclo (Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo (Asp-Ser)], cyclohexyl amide Amine acid [Cyclo(Lys-Tyr)], cyclosamine, aspartic acid [Cyclo(Arg-Asp)], cycloamine decyl phenyl Amino acid [Cyclo(Leu-Phe)], cycloglyoxime thioglycolic acid [Cyclo(Gln-Ser)], cyclohexyl phenylalanine [Cyclo(Lys-Phe)], ring bran Amine-based leucine [Cyclo(Gln-Leu)], cyclopropylamino phenylalanine [Cyclo(Ala-Phe)], cyclosamine phenyl phenylalanine [Cyclo(Arg-Phe)], Cyclo(Arg-Tyr), Cyclo(Lys-Ser), Cyclo(Gly-Lys), cycloalkylamine tyrosine And one or more of the group consisting of cyclopropylamine decyl glutamate [Cyclo(Ala-Val)].

According to the present invention, a composition having excellent melanin-aggregating hormone receptor antagonism can be provided. By using the composition of the melanin-concentrating hormone receptor antagonist of the present invention in an arbitrary administration method, prevention or treatment of obesity, obesity-related diseases, hypermetabolism, improvement of eating disorders, or appetite suppression can be obtained. effect.

1. Melanin aggregation hormone and melanin aggregation hormone receptor antagonism

In the present specification, "melanin-concentrating hormone" is a cyclic neuropeptide composed of 19 amino acid which is expressed in a large amount in the hypothalamus under mammals, and its name (Melanin Concentrating Hormone) is also called MCH. In addition, in the present specification, the term "melanin-concentrating hormone receptor antagonism" means antagonism of adhesion to melanin-concentrating hormone receptors with melanin-concentrating hormones. In order to prevent the binding of melanin-concentrating hormones, the composition having such an antagonistic action is called "melanin-concentrating hormone receptor antagonist composition". There are two subtypes of melanin-concentrating hormone receptors, which are called type 1 receptor (MCH1R) and type 2 receptor (MCH2R). The melanin-concentrating hormone receptor in the present invention contains any one of the subtypes, but is preferably a type 1 receptor (MCH1R).

Melanin-concentrating hormone receptor antagonism can be assessed according to well-known methods. For example, a cell expressing a melanin-concentrating hormone receptor can be used to measure a change in the intracellular calcium ion concentration when a melanin-concentrating hormone is added, and the measured value in the presence of the sample and in the absence of the sample can be compared. More specifically, the lower the measured value in the presence of the sample relative to the measured value in the absence of the sample (that is, the change in the intracellular calcium ion concentration is small), the greater the melanin-concentrating hormone receptor antagonism can be evaluated.

2. Cyclic dipeptide

The term "cyclic dipeptide" as used in the present specification means a ring having a structure of a diketopiperazine formed by dehydration condensation of an amino group of an amino acid with a carboxyl group, which is characterized by an amino acid as a constituent unit. Dipeptide. Therefore, the cyclic dipeptide differs from the chain dipeptide. Further, in the present specification, a cyclic dipeptide or a salt thereof may be integrated, and it may be simply referred to as a cyclic dipeptide. Further, in the present specification, as long as the amino acid structure of the cyclic dipeptide is the same, the order of description may be any first, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)]. Represents the same cyclic dipeptide.

Because the cyclic dipeptide binds to the two amino acids through the indole bond The terminal portion (that is, the cyclic dipeptide has a cyclic structure in which an amine terminal and a carboxyl terminal are bonded by a guanamine bond), and a linear or a linear group in which a polar group is exposed at a terminal portion of the molecule Peptides (especially linear dipeptides composed of the same amino acid composition) are characterized by high fat solubility compared to cyclic dipeptides. Therefore, the cyclic dipeptide is superior in digestive tract permeability or membrane permeability to a linear dipeptide. This is understood by the results of the past test of the compound permeation test using the rat to reverse the intestine (J. Pharmacol, 1998, 50: 167-172). Furthermore, it is believed that cyclic dipeptides also increase their tolerance to various peptidases due to their specific structure.

The cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention is selected from the group consisting of cyclosqualamine leucine, [Cyclo(Arg-Leu)], and cycloglycine thiol arginine [Cyclo(Gln). -Arg)], cycloalkyrosine lysine (Cyclo (Leu-Lys)], cyclopropylamine decyl leucine [Cyclo (Ala-Leu)], cycloaspartic acid sulfhydryl amide (Cyclo (Cyclo (Ala-Leu)] Asp-Ser)], cyclohexyl tyrosine [Cyclo(Lys-Tyr)], cyclosamine decyl aspartate [Cyclo(Arg-Asp)], cycloalkyrosyl phenylalanine [Cyclo(Leu-Phe)], cycloglycine thioglycolic acid [Cyclo(Gln-Ser)], cyclohexyl phenylalanine [Cyclo(Lys-Phe)], cycloglyoxime oxime Lysine [Cyclo(Gln-Leu)], cyclopropylaminophenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], ring essence Aminoguanidine tyrosine [Cyclo(Arg-Tyr)], cyclohexylamine sulphate [Cyclo(Lys-Ser)], cycloglycine cis-amino acid [Cyclo(Gly-Lys)], and One or more of the group consisting of cyclopropylamine decyl glutamic acid [Cyclo(Ala-Val)]. The number of the cyclic dipeptide or a salt thereof is not particularly limited, but in the present invention, the ring is Three or more selected from the dipeptide or a salt thereof are preferred as the active ingredient. Further, the cyclic dipeptide or a salt thereof is selected from the group consisting of cyclo arginyl lysine [Cyclo(Arg-Leu)], cyclohexane lysine ( Cyclo(Lys-Ser)], Cyclo(Gln-Arg), Cyclo(Leu-Lys), Cyclo(Ala-Leu) Cyclo(Asp-Ser), Cyclo(Lys-Tyr), cyclosamine, Cyclo-Argyr One or more of Asp)] and cycline phenylalanine [Cyclo(Leu-Phe)] are preferably selected from the group consisting of cyclosamine decyl leucine [Cyclo (Arg) -Leu)], Cyclohexylamine, Cyclo(Lys-Ser), Cyclo(Gln-Arg), and cycline-based lysine One or two or more of the groups of [Cyclo(Leu-Lys)] are more preferable.

In the present specification, the "salt of a cyclic dipeptide" means any salt (including an inorganic salt and an organic salt) which is pharmacologically acceptable as the above-mentioned cyclic dipeptide, and examples thereof include the above-mentioned cyclic dipeptide. Sodium, potassium, calcium, magnesium, ammonium, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalic acid) Salt, lactate, succinate, fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, etc., but not limited thereto . Salts of cyclic dipeptides can be readily prepared by the manufacturer by any method known in the art.

The cyclic dipeptide system used in the present invention can be prepared by a method well known in the art. For example, by chemical synthesis or enzymatic methods, It can be produced by a microbial fermentation method, or can be synthesized by dehydrating and cyclizing a linear peptide, and can be prepared according to the method described in JP-A-2003-252896 or Journal of Peptide Science, 10, 737-737, 2004. . For example, the peptide of the plant is automatically subjected to high-temperature heat treatment by subjecting the raw material of the protein containing the autologous plant to the enzyme treatment or heat treatment, thereby obtaining a peptide heat-treated product of the auto-plant which is rich in the cyclic dipeptide. From the viewpoint of the above, the cyclic dipeptide or a salt thereof used in the present invention may be a chemical or biological synthetic compound or a peptide derived from an automated plant.

3. Come to auto plant peptides

The "peptide for automatic plant" in the present specification is not particularly limited, and for example, soybean peptide, tea peptide, malt peptide, lactopeptide, placental peptide, collagen peptide or the like can be used. Among these, soybean peptide and tea peptide are preferred in the present invention. The peptide of the automatic plant can be prepared by using a protein derived from an automatic plant or a material containing a protein, or a commercially available product.

3-1. Soy peptide

The "soybean peptide" as used herein refers to a low molecular peptide obtained by subjecting soybean protein to an enzyme treatment or heat treatment to lower the molecular weight of the protein. As a raw material, soybean (scientific name: Glycine max) can be used without restrictions such as variety and place of production, and a processed product such as a pulverized product can also be used.

3-2. Tea peptide

The term "tea 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 leaf residue) extract to an enzyme treatment or heat treatment to lower the molecular weight of the protein. As the tea leaves to be used as the extraction raw material, the leaves and stems of the tea leaves produced by the tea tree (scientific name: Camellia sinensis) can be used, and the drinkable parts can be used. Further, the form is not limited to whole leaves, powders, and the like. For the harvest period of the tea, it can also be appropriately selected in accordance with the desired aroma.

3-3. Malt peptide

The term "malt peptide" as used herein refers to a low molecular peptide derived from malt obtained by subjecting an extract obtained from malt or a ground product thereof to an enzyme treatment or heat treatment to lower the molecular weight of the protein. The malt peptide which is a raw material can be used without limitation, such as a variety and a production place, but it is especially suitable to use the barley malt which has germinated the barley seed. In addition, barley malt is sometimes only abbreviated as malt in this specification.

3-4. Milk peptide

The term "milk peptide" as used herein refers to a molecule in which milk proteins derived from natural milk are decomposed into molecules in which at least a plurality of amino acids are bonded. More specifically, milk protein such as whey (whey protein) or casein may be hydrolyzed by an enzyme such as protease, and the filtrate obtained by filtration may be sterilized and/or concentrated and dried. Whey peptide, casein peptide, and the like.

3-5. Placental peptide

The so-called placenta refers to the placenta of mammals. Due to its excellent functionality, it has been used as a health food, cosmetics, and pharmaceutical materials in recent years. The term "placental peptide" as used herein refers to a method in which a placenta is subjected to an enzyme treatment or a subcritical treatment to be solubilized and reduced in molecular weight. Further, unlike the original meaning, the extract obtained from the placenta of the plant is used as a health food, a cosmetic, or the like as a physiological placebore of the placenta from the placenta, and is referred to as a plant placenta. The "placental peptide" in the present specification also includes a method in which a plant placenta is subjected to an enzyme treatment or a subcritical treatment to be solubilized and reduced in molecular weight.

3-6. Collagen peptide

The term "collagen peptide" as used herein refers to a low molecular peptide obtained by subjecting collagen or a pulverized material thereof to treatment with an enzyme or heat treatment to reduce the molecular weight of collagen. Collagen is the main protein of animal connective tissue and contains the most protein in the body of human mammals.

4. Automatic peptide heat treatment of plants

As described above, a peptide heat-treated product of an autonomic plant rich in a cyclic dipeptide can be obtained by subjecting a peptide of an automatic plant to high-temperature heat treatment in the future. In the present specification, the term "high-temperature heat treatment" means that the treatment is carried out for a predetermined period of time at a temperature of 100 ° C or higher and a pressure exceeding atmospheric pressure. As a high-temperature and high-pressure treatment device, a pressure-resistant extraction device or pressure can be used in combination with conditions. Pot, high pressure steam sterilizer, etc.

The temperature in the high-temperature heat treatment is not particularly limited as long as it is 100 ° C or higher, but is preferably 100 ° C to 170 ° C, more preferably 110 ° C to 150 ° C, still more preferably 120 ° C to 140 ° C. Further, at this temperature, when the pressure-resistant extraction device is used as the heating device, the value of the outlet temperature of the extraction column is measured, and when the high-pressure steam sterilizer is used as the heating device, the value of the temperature at which the center temperature in the pressure vessel is measured is indicated.

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

The high-temperature heat treatment time is not particularly limited as long as it can obtain a treatment containing a cyclic dipeptide, but it is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably 60 minutes. ~300 minutes or so.

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, but it is preferably [temperature: pressure: time]: [100 ° C to 170 ° C: 0.101 MPa. ~0.79MPa: 15 minutes~600 minutes], more preferably [110°C~150°C: 0.101MPa~0.60MPa: 30 minutes~500 minutes], and even more preferably [120°C~140°C: 0.101MPa~0.48MPa) : 60 minutes to 300 minutes].

In addition, the peptide heat-treated product of the obtained automatic plant can be filtered, centrifuged, concentrated, ultra-filtered, and cooled as desired. Treatment by freeze drying, powdering, and the like. In addition, when the specific cyclic dipeptide in the peptide heat-treated product of the automatic plant does not satisfy the desired content, other specific cyclic dipeptides may be added as appropriate, or other commercially available peptides, commercially available products, or synthetic products may be used.

5. Melanin-concentrating hormone receptor antagonistic composition 5-1. Cyclic dipeptide contains melanin-concentrating hormone receptor antagonistic composition

One aspect of the present invention is a melanin-concentrating hormone receptor antagonist composition comprising a specific cyclic dipeptide or a salt thereof as an active ingredient.

The composition for melanin-concentrating hormone receptor antagonist of the present invention comprises a compound selected from the group consisting of cyclo arginyl leucine [Cyclo(Arg-Leu)], cyclophosphamide arginine [Cyclo(Gln-Arg)], Cyclo(Leu-Lys), Cyclo(Ala-Leu), Cyclo(Asp-Ser) Cyclo (Lys-Tyr), cyclosylamine aspartic acid [CYclo(Arg-Asp)], cycloalkonyl phenylalanine [Cyclo (Leu-) Phe)], cycloglycine 醯 丝 丝 serine acid [Cyclo (Gln-Ser)], cyclohexyl phenyl phenylalanine [Cyclo (Lys-Phe)], cycloglutamine decyl leucine [ Cyclo(Gln-Leu)], cyclopropylaminophenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine decyl tyramine Acid [Cyclo(Arg-Tyr)], cyclohexylamine sulphate [Cyclo(Lys-Ser)], cycloglycidyl phthalic acid [Cyclo(Gly-Lys)], and cyclopropylamine hydrazide One or two or more kinds of cyclic dipeptides or a salt thereof in a group of aminic acid [Cyclo(Ala-Val)] are used as an active ingredient. Melanin-concentrating hormone receptor antagonist of the present invention The number of the cyclic dipeptide or the salt thereof to be contained in the composition is not particularly limited, but in the present invention, it is preferred to include three or more selected from the above cyclic dipeptide or a salt thereof. The cyclic dipeptide or a salt thereof is selected from the group consisting of cyclosqualamine leucine, Cyclo (Arg-Leu), Cyclo (Lys-Ser), and ring bran Aminoguanidine arginine [Cyclo(Gln-Arg)], cycloalkyrosine lysine (Cyclo (Leu-Lys)], Cyclopropylamine leucine (Cyclo (Ala-Leu)], ring-day Cyclo(Asp-Ser), Cyclo(Lys-Tyr), Cyclo(Arg-Asp) And one or more selected from the group consisting of Cyclo(Leu-Phe), selected from the group consisting of cyclosamine, arginyl leucine [Cyclo(Arg-Leu) ], Cyclo(Lys-Ser), Cyclo(Gln-Arg), and Cycloamine Cyclo (Leu) -Lys)] One or more of the groups are more preferably.

The content of the cyclic dipeptide or a salt thereof in the composition for melanin-concentrating hormone receptor antagonist of the present invention may be any amount as long as it can obtain the desired effect of the present invention in consideration of the administration form, the administration method, and the like. There is no particular limitation. For example, when a soybean peptide, a tea peptide, a malt peptide, a lactopeptide, a placental peptide, or a collagen peptide is used as a raw material, the total amount of the cyclic dipeptide or a salt thereof in the composition of the present invention is 200 ppm/Brix. The above is preferably 300 ppm/Brix or more; 5000 ppm/Brix or less, preferably 4000 ppm/Brix or less, and typically 200 to 5000 ppm/Brix, preferably 300 to 4000 ppm/Brix. Further, as a composition for the melanin-concentrating hormone receptor antagonist of the present invention, cyclosamine arginine leucine [Cyclo(Arg-Leu)], a ring Glutenin thiol arginine [Cyclo(Gln-Arg)], cycloalkyrosine Cyclo (Leu-Lys), Cyclo(Ala-Leu), Cyclo(Asp-Ser), Cyclo(Lys-Tyr), Cyclo-Argin, Cyclo(Arg-Asp) )], cycloalbenyl phenylalanine [Cyclo(Leu-Phe)], cycloglutamine thioglycolic acid [Cyclo(Gln-Ser)], cyclohexyl phenyl phenylalanine [Cyclo (Lys-Phe)], cycloglutamine decyl leucine [Cyclo(Gln-Leu)], cyclopropylaminophenyl phenylalanine [Cyclo(Ala-Phe)], cyclosamine decyl phenyl propylamine Acid [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], cyclohexylamine sulphate [Cyclo(Lys-Ser)], cycloglycine guanidine The content of the amine [Cyclo(Gly-Lys)], cyclopropylamine decylamine [Cyclo(Ala-Val)], or a salt thereof is 1.0 ppm/Brix or more, preferably 3.0 ppm/ Brix or more; 3000 ppm/Brix or less, preferably 2000 ppm/Brix or less, typically 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 Brix (Brei: Bx) as described above. The "amount per Brix" in the present specification means an amount specified by a value equivalent to a mass percentage of a sucrose solution (containing only sucrose as a solute) of 20 °C. In addition, unless otherwise specified, the "ppm" used in this specification means the ppm of weight/capacity (w/v), and 1.0 ppm/Brix is converted into 0.1 mg/mL when the specific gravity of the solvent is 1, and is converted. It is 0.01% by weight.

The content of the cyclic dipeptide or a salt thereof can be measured by a known method. For example, the measurement can be carried out using an LC-MS/MS or a saccharometer.

In addition, the composition for melanin-concentrating hormone receptor antagonist of the present invention may contain, as an active ingredient, a heat-treated peptide of an auto-plant containing one or more of the above-described cyclic dipeptide or a salt thereof. The peptide heat-treated product of the automatic plant is not particularly limited, but the soybean peptide heat-treated product and the tea peptide heat-treated product are preferred.

When the peptide heat-treating material of the plant is used, the content of the melanin-concentrating hormone receptor antagonist composition of the present invention, in consideration of the administration form, the administration method, and the like, is the amount which can obtain the desired effect of the present invention. However, it is not particularly limited. 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 composition for melanin-concentrating hormone receptor antagonist 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 thereof. Examples of such additives and/or components include physiologically active ingredients such as vitamins E, vitamin C, vitamins, minerals, nutrients, and flavors, as well as those formulated in the formulation. Agent, binder, emulsifier, tonicity agent (isoterizing agent), buffer, dissolution aid, preservative, stabilizer, antioxidant, colorant, coagulant, or coating agent, etc., but not limited This is the case.

5-3. Use

The melanin-concentrating hormone receptor antagonist composition of the present invention is characterized by containing the above-mentioned active ingredient, which can antagonize the binding of the melanin-concentrating hormone receptor to its receptor. As described above, since the melanin-concentrating hormone receptor includes a subtype of MCH1R and MCH2R 2, the composition of the present invention may be a composition for MCH1R (MCH1 receptor) antagonist and/or a composition for MCH2R (MCH2 receptor) antagonist.

The aforementioned active ingredient contained in the melanin-concentrating hormone receptor antagonist composition of the present invention can effectively prevent or treat diseases related to obesity, obesity-related diseases, and hypermetabolism by blocking the binding of melanin-concentrating hormone to its receptor. , improvement in eating disorders, or appetite suppression. Therefore, the composition of the present invention is a composition for preventing or treating obesity, diseases related to obesity, hypermetabolism, improvement of eating disorders, or melanin-concentrating hormone receptor antagonistic for appetite suppression. The melanin-concentrating hormone receptor antagonist composition of the present invention can be used as a composition for preventing or treating obesity, a composition for preventing or treating diseases related to obesity, a composition for metabolism and a composition for improving eating disorders, and the like. Or an appetite suppressing composition. Here, the disease related to obesity is not particularly limited, but examples thereof include diabetes, hyperlipidemia, hypertension, arteriosclerosis, myocardial infarction, cerebral infarction, fatty liver, and knee osteoarthritis. In addition, in the "prevention" and "treatment", the concept of "preventing" and "treating" includes a state in which it is better than the current state and a state in which it is made worse than the current state, and improvement, recovery, reduction, relaxation, etc. Terms can also be included here.

The melanin-concentrating hormone receptor antagonist composition of the present invention can be formulated into a solid preparation such as a tablet, a granule, a powder, a powder, or a capsule by a known method, for example, using the above-mentioned other components, and the like. a liquid agent such as a dose, a suspension, or an emulsion. These compositions can be taken directly with water or the like. Further, after being prepared into a form that can be easily formulated (for example, a powder form or a particle form), for example, a raw material for a pharmaceutical product can be used.

The melanin-concentrating hormone receptor antagonist composition of the present invention may be provided as an example, but is not limited to the present embodiment. The aforementioned agent may be directly provided as a composition or as a composition containing the aforementioned 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. Examples of the non-food composition limitation include functional foods, health supplement foods, nutritional function foods, special purpose foods, specific health foods, nutritional supplement foods, therapeutic foods, health foods, nutritional supplements, and food additives. Wait.

The melanin-concentrating hormone receptor antagonist composition of the present invention can be suitably used for therapeutic use (medical use) or non-therapeutic use (non-medical use). Specifically, it can be exemplified by pharmaceuticals, quasi-drugs, cosmetics, and the like, and it is not included in the pharmaceutical law, and it is an expressive or suggestive appeal for energy production promotion, weight gain suppression, organ fat accumulation inhibition, muscle increase, The use of a composition such as a reduction in muscle atrophy, or a preventive or therapeutic effect of an optic nerve disorder.

Another aspect of the invention relates to the inclusion of melanin A composition for modulating the melanin-concentrating hormone receptor antagonist of the function of the hormone receptor antagonism. The labeling or the functional labeling 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 " Increase the energy consumption in the body, "promote the decomposition of body fat", "become easy to consume fat", "promote the burning of fat", "improve the eating disorder", "suppress appetite", "make metabolism", The description of the equivalent meaning of "inhibition of dietary intake" and the like is also included in the label. In this specification, the label of the label and the functional label may be attached to the composition itself or may be attached to the container or package of the composition.

The melanin-concentrating hormone receptor antagonist composition of the present invention can be ingested by an appropriate method depending on the form thereof. The method of ingestion is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can migrate to circulating blood. For example, it may be an oral liquid preparation, an injection preparation, an external preparation, or a suppository for a oral solid preparation, an internal liquid preparation, or a syrup preparation such as a tablet, a lozenge, a granule, a powder, or a capsule. Or a form of a non-oral preparation such as a percutaneous absorption agent, but is not limited thereto. In addition, the term "ingestion" as used in this specification refers to the use of an all-inclusive form including ingestion, administration, or drinking.

The applicable amount of the melanin-concentrating hormone receptor antagonist 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 subject to be administered, and is not necessarily constant. Although the effective human intake of the composition of the present invention is not constant, for example, the weight of the cyclic dipeptide or its salt as an active ingredient thereof, and a body weight of 50 kg The human is preferably 10 mg or more per day, more preferably 100 mg or more. Further, the administration can be carried out in a single or divided number of times within one day within the range of the desired dosage. The period of investment is also arbitrary. In addition, the effective human intake amount of the composition of the present invention refers to the intake amount of the melanin-concentrating hormone receptor antagonist composition of the present invention which exhibits an effective effect in humans.

The subject of the melanin-concentrating hormone receptor antagonist composition of the present invention is preferably a human, but a livestock animal such as a cow, a horse, a goat, a pet animal such as a dog, a cat, or a rabbit, or a mouse or a rat. Experimental animals such as guinea pigs and monkeys are also available. When the animal is administered to an animal other than human, the amount of use per day of the individual mouse is about 20 g per day, depending on the content of the active ingredient in the composition, the state of the subject, the body weight, the sex, and the age. In general, the total amount of the cyclic dipeptide or a salt thereof is preferably an amount of 10 mg/kg or more, more preferably 100 mg/kg or more.

6. Use of a cyclic dipeptide or a salt thereof for blocking the binding of melanin-concentrating hormone to its receptor

One aspect of the present invention is the use of an amino acid as a constituent unit of a specific cyclic dipeptide or a salt thereof for inhibiting the binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor. Preferably, it is selected from the group consisting of cyclosamine, arginine, Cyclo (Arg-Leu), cyclophosphamide, Cyclo(Gln-Arg), cyclophosphamide, lysine, Cyclo (Leu-Lys)], cyclopropylamine-based leucine [Cyclo(Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo(Asp-Ser)], cyclohexylamine tyrosine [ Cyclo(Lys-Tyr)], Cyclo(Arg-Asp), cycloallinyl phenylalanine [Cyclo(Leu-Phe)], cycloglycine thioglycolic acid [Cyclo(Gln-) Ser)], cyclohexyl phenylalanine [Cyclo(Lys-Phe)], cycloglutamine decyl leucine [Cyclo(Gln-Leu)], cyclopropylamine phenyl phenylalanine [Cyclo (Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], cycloamine amide-based serine One of a group of [Cyclo(Lys-Ser)], cycloglycine, Cyclo(Gly-Lys), and Cyclo(Ala-Val) or The use of two or more cyclic dipeptides or salts thereof to inhibit the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor. More preferably, it is used to contain a combination of three or more selected from the above-mentioned cyclic dipeptides or salts thereof for inhibiting the binding of melanin-concentrating hormones to their receptors.

In the use of the present invention, for example, the use of the above-mentioned cyclic dipeptide or a salt thereof for preventing or treating obesity, diseases related to obesity, hypermetabolism, improvement of eating disorders, or appetite suppression is not limited thereto. This is the case. Moreover, the use is for use in human or non-human animals and may be therapeutic for non-therapeutic use. Here, "non-therapeutic" refers to the concept of not treating medical behavior, that is, treating the behavior of the human body.

7. A method of blocking the binding of melanin-concentrating hormone to its receptor

One aspect of the present invention is a method for inhibiting the binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor using an amino acid as a constituent unit of a specific cyclic dipeptide or a salt thereof as an active ingredient. Preferably, the method comprises Used in the group consisting of Cyclo (Arg-Leu), Cyclo(Gln-Arg), cycline, and Cyclo (Leu) -Lys)], cyclopropylamine-based leucine [Cyclo(Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo(Asp-Ser)], cyclohexylamine tyrosine [Cyclo(Cyclo(S)) Lys-Tyr)], cyclosamine, aspartic acid [Cyclo(Arg-Asp)], cycloalkyrosine phenylalanine [Cyclo (Leu-Phe)], cycloglycosyl thiol amide Acid [Cyclo(Gln-Ser)], cycloalkylaminophenylalanine [Cyclo(Lys-Phe)], cycloglutamine decyl leucine [Cyclo(Gln-Leu)], cyclopropylamine thiol Phenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], cyclization Amino-mercapto-serine [Cyclo(Lys-Ser)], cycloglycine guanidine-amino acid [Cyclo(Gly-Lys)], and cyclopropylamine-proline glutamic acid [Cyclo(Ala-Val)] A method in which one or two or more cyclic dipeptides or a salt thereof in the group are used as an active ingredient to inhibit binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor. More preferably, it comprises a method of blocking the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor using three or more selected from the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient.

Other aspects associated with this method include the administration of a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient to a subject in need of blocking the binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor. A method of binding a melanin-concentrating hormone to a melanin-concentrating hormone receptor. Preferably, it comprises administering a therapeutically effective amount selected from the group consisting of Cyclo(Arg-Leu), Cyclo(Gln-Arg), Cycloamine Sulfhydryl acid [Cyclo(Leu-Lys)], Cyclopropylamino leucine [Cyclo(Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo(Asp-Ser)], cycloalkylamine tyrosine [Cyclo(Lys-Tyr)] Cyclo(Arg-Asp), cycloallinyl phenylalanine [Cyclo(Leu-Phe)], cycloglutamine thioglycolic acid [Cyclo(Gln) -Ser)], cyclohexyl phenylalanine [Cyclo(Lys-Phe)], cycloglutamine decyl leucine [Cyclo(Gln-Leu)], cyclopropylaminophenyl phenylalanine [ Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], cyclized amine sulfhydryl amide One of a group of acids [Cyclo(Lys-Ser)], cycloglycine guanidine lysine [Cyclo(Gly-Lys)], and cyclopropylamine decylamine [Cyclo(Ala-Val)] Or a method in which two or more cyclic dipeptides or a salt thereof is used as an active ingredient to inhibit binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor. More preferably, it is a method comprising administering a therapeutically effective amount of three or more selected from the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient, which inhibits binding of a melanin-concentrating hormone to its receptor.

In the above method, the subject to which the binding of the melanin-concentrating hormone to the receptor is required is the same as the above-mentioned application target of the melanin-concentrating hormone receptor antagonist composition of the present invention. In addition, the therapeutically effective amount in the present specification means that when the melanin-concentrating hormone receptor antagonist composition of the present invention is administered to the above-mentioned subject, the receptor for melanin-concentrating hormone is inhibited as compared with the unadministered subject. The amount of the combination. The specific effective amount may be appropriately set depending on the administration form, the administration method, the purpose of use, and the age, body weight, symptoms, and the like of the subject, and is not constant.

In the method of the present invention, the therapeutically effective amount is The above-mentioned specific cyclic dipeptide or a salt thereof may be administered as it is, or it may be administered as a composition containing a specific cyclic dipeptide or a salt thereof.

According to the method of the present invention, the binding of melanin-concentrating hormone to its receptor can be inhibited without causing side effects.

[Examples]

In the following, the present invention will be described in further detail by way of examples, without limiting the scope of the invention. The use of the method of the present invention in various modifications and changes is intended to be included within the scope of the present invention.

Example 1. Study on the antagonism of melanin-concentrating hormone receptor (MCH1R) induced by cyclic dipeptide

In order to investigate the antagonism in the melanin-concentrating hormone receptor of the cyclic dipeptide sample, a binding test to the melanin-concentrating hormone receptor (MCH1R) was carried out. Specifically, CHO cells expressing human MCH1R (cells derived from Chinese hamster ovary) were used, and 30 μM of human MCH and various concentrations of chemically synthesized cyclic dipeptide samples were added thereto to measure changes in intracellular calcium ion concentration. . The intracellular calcium ion concentration was quantified by fluorescence photometric analysis.

Regarding the antagonism of the cyclic dipeptide to be tested, the reaction rate (change in intracellular calcium ion concentration) when no cyclic dipeptide was added and only human MCH was added was taken as 100%, and the relative value (%) was used to calculate the addition of a cyclic ring. The reaction rate of the dipeptide with human MCH, the difference (the fraction reduced by 100%) The impediment rate (%) indicates that the assessment is performed. The results are shown in Table 1.

From the above results, it is understood that the cyclic dipeptides shown in Table 1 all have melanin-concentrating hormone receptor antagonism.

Example 2. Study on the antagonism of melanin-aggregating hormone receptor (MCH1R) induced by heat treatment of tea peptide and heat treatment of soybean peptide (1) Modification of heat treatment of tea peptide

As a plant body, one of Kagoshima's products is used as a tea leaf (variety: Yubei, total nitrogen: 6.3%). For this tea, the treatment of the water-soluble protein was first carried out (extraction 3 times before). That is, 200 g of hot tea was added to 10 g of tea leaves, and the mixture was appropriately stirred, and extraction was carried out for 5 minutes. After the end of the extraction, the mixture was filtered through 140 mesh to recover the extraction residue (tea leaves). This tea residue was poured into 200 g of hot water for 5 minutes to extract and recover the tea residue. Once again, the tea leaves are subjected to the same extraction treatment to recover the tea leaves.

Next, the tea leaves (tea leaves) which have been subjected to the previous extraction are subjected to decomposition treatment with an enzyme. 200 g of hot water of 50 ° C was poured into tea leaves (total amount), and 1 g of protease (trade name: Protin NY100, manufactured by Daiwa Kasei Co., Ltd.) was added, and the mixture was stirred (300 rpm) with a stirrer, and reacted in a water bath at 55 ° C. hour. Thereafter, the enzyme was inactivated by holding at 95 ° C for 30 minutes.

This enzyme treatment liquid is subjected to heat treatment in the form of a liquid mixture of tea leaves without solid-liquid separation. The heat treatment was carried out by a high-pressure steam sterilizer (manufactured by TOMY Seiko Co., Ltd.), and heat treatment was carried out at 135 ° C for 3 hours. The treated liquid was filtered through 140 mesh to obtain a heat treatment of the tea peptide.

(2) Modulation of heat treatment of soybean peptide

As the heat treatment material of the soybean peptide, a person who heats the soybean peptide is used. The soybean peptide heat treatment system is produced by subjecting the soybean peptide to high temperature and high pressure treatment in a liquid. Specifically, about 15 ml of distilled water was added to 3 g of soybean peptide (HINUTE AM, manufactured by Fuji Oil Company), and high pressure steam was placed. The sterilizer (manufactured by TOMY Seiko Co., Ltd.) was subjected to high temperature and high pressure treatment at 135 ° C, 0.31 MPa, and 3 hours.

(3) Evaluation of melanin-concentrating hormone receptor (MCH1R) antagonism

In order to investigate the antagonism of the heat treatment of the tea peptide and the melanin-concentrating hormone receptor of the heat-treated soybean peptide, a binding test to the melanin-concentrating hormone receptor (MCH1R) was carried out. Specifically, CHO cells expressing human MCH1R (cells derived from Chinese hamster ovary) were used, and human MCH (30 μM) and heat treatment of tea peptide heat treatment or soybean peptide were added thereto (final concentration was 0.1 mg/ml or 1 mg). /ml), the change in intracellular calcium ion concentration was measured. The intracellular calcium ion concentration was quantified by fluorescence photometric analysis. The heat-treated product of the heat treatment of the tea peptide and the heat-treated product of the soybean peptide is subjected to spray drying treatment of the heat-treated product described in each of the above (1) and (2).

Regarding the antagonism of the heat treatment of the tea peptide and the heat treatment of the soybean peptide, the reaction rate (change in intracellular calcium ion concentration) when the heat treatment of the tea peptide and the heat treatment of the soybean peptide were not added and only the human MCH was added was taken as 100%, and the relative Value (%) The reaction rate when the heat treatment of the tea peptide heat treatment or the soybean peptide heat treatment was added to the human MCH was calculated, and the difference (the portion reduced by 100%) was expressed as the inhibition rate (%), and was evaluated. The results are shown in Table 2.

From the above results, it is understood that both the heat treatment of the tea peptide and the heat treatment of the soybean peptide have melanin-aggregating hormone receptor (MCH1R) antagonism. In the melanin-concentrating hormone receptor (MCH1R) antagonistic effect of these test materials, it is considered that the cyclic dipeptide contained in various materials (for example, the cyclic dipeptide shown in Table 1) contributes to one of the factors. Sex.

[Industrial availability]

The present invention provides a melanin-concentrating hormone receptor antagonist composition comprising a specific cyclic dipeptide or a salt thereof as an active ingredient. Since the present invention provides a novel means for contributing to the prevention of obesity and the like, it is highly industrially usable.

Claims (8)

A melanin-concentrating hormone receptor antagonist composition comprising a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, and the cyclic dipeptide or a salt thereof is selected from the group consisting of cyclospermine Cyclo [Arg (L-Leu)], cyclophosphamide arginine sulphate [Cyclo(Gln-Arg)], cyclic leucine lysine (Cyclo (Lcu-Lys)], cyclopropylamine Lysine [Cyclo(Ala-Leu)], Cyclo(Asp-Ser), Cyclo(Lys-Tyr), Cyclosporin Amino-mercapto aspartic acid [Cyclo(Arg-Asp)], cycloalkyrosine phenylalanine [Cyclo(Leu-Phe)], cycloglutamine thioglycolic acid [Cyclo(Gln-Ser)] ], Cyclo(Lys-Phe), Cyclo(Gln-Leu), Cyclopropylaminophenylalanine [Cyclo(Ala) -Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], cyclized amine arginine dextran [Cyclo (Lys-Ser)], one or two of the group consisting of Cyclo(Gly-Lys) and Cyclo(Ala-Val) the above. The melanin-concentrating hormone receptor antagonist composition according to claim 1, which is for anti-obesity, prevention or treatment of diseases associated with obesity, metabolic hyperactivity, improvement of eating disorders, or appetite suppression. The melanin-concentrating hormone receptor antagonist composition according to claim 1 or 2, wherein the cyclic dipeptide or a salt thereof is derived from a peptide of an automatic plant. The melanin-concentrating hormone receptor antagonist composition according to any one of claims 1 to 3, which is characterized by a function exerted by melanin-concentrating hormone receptor antagonism. The melanin-concentrating hormone receptor antagonist composition according to claim 4, wherein the function is marked by "prevention of obesity", "improvement of obesity", "inhibition of weight gain", "inhibition of accumulation of body fat", "inhibition of internal organs" "Accumulation of fat", "increasing energy consumption in the body", "promoting the decomposition of body fat", "fabricating fat", "promoting fat burning", "improving eating disorders", "suppressing appetite", Choose from the group that "make metabolism" and "inhibition of diet intake". The melanin-concentrating hormone receptor antagonist composition according to any one of claims 1 to 5, wherein the composition is an agent. A cyclic dipeptide or a salt thereof comprising an amino acid as a constituent unit for inhibiting binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor, characterized in that the cyclic dipeptide or a salt thereof comprises a ring selected from the group consisting of Cyclo(Arg-Leu), Cyclo(Gln-Arg), Cyclo(Leu-Lys) Cyclo(Ala-Leu), Cyclo(Asp-Ser), Cyclo(Lys-Tyr) ], cyclosamine, aspartic acid [Cyclo (Arg-Asp)], cycloalkyrosine phenylalanine [Cyclo (Leu-Phe)], cycloglyoxime thioglycolic acid [Cyclo ( Gln-Ser)], cyclohexyl phenylalanine [Cyclo(Lys-Phe)], cycloglutamine decyl leucine [Cyclo(Gln-Leu)], cyclopropylamine Phenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine thiol tyrosine [Cyclo(Arg-Tyr)], ring From Cyclo(Lys-Ser), Cyclo(Gly-Lys), and Cyclo(Ala-Val) One or two or more of the groups. A method of using a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient, which inhibits binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor, and is characterized by the aforementioned cyclic dipeptide or The salt thereof is selected from the group consisting of cyclosamine, arginyl leucine [Cyclo(Arg-Leu)], cycloglycine thiol arginine [Cyclo(Gln-Arg)], cyclic leucine guanidine lysine [Cyclo (Leu-Lys)], cyclopropylamine-based leucine [Cyclo(Ala-Leu)], cycloaspartic acid thioglycolic acid [Cyclo(Asp-Ser)], cyclohexylamine tyrosine [ Cyclo(Lys-Tyr)], cyclosamine, aspartic acid, Cyclo(Arg-Asp), cycloallinyl phenylalanine, Cyclo(Leu-Phe), cycloglyoxime Cyclo(Gln-Ser), Cyclo(Lys-Phe), Cyclo(Gln-Leu), Cyclopropylamine Nonylphenylalanine [Cyclo(Ala-Phe)], cyclosamine phenylphenylalanine [Cyclo(Arg-Phe)], cyclosamine tyrosine [Cyclo(Arg-Tyr)], Cyclo(Lys-Ser), Cyclo(Gly-Lys), and Cyclopropylamine a-Val)] One or two or more of the groups.