JP6687619B2 - Composition for antagonisting melanin-concentrating hormone receptor - Google Patents
Composition for antagonisting melanin-concentrating hormone receptor Download PDFInfo
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- JP6687619B2 JP6687619B2 JP2017529567A JP2017529567A JP6687619B2 JP 6687619 B2 JP6687619 B2 JP 6687619B2 JP 2017529567 A JP2017529567 A JP 2017529567A JP 2017529567 A JP2017529567 A JP 2017529567A JP 6687619 B2 JP6687619 B2 JP 6687619B2
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- melanin
- concentrating hormone
- hormone receptor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/82—Theaceae (Tea family), e.g. camellia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
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- Microbiology (AREA)
- Mycology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Peptides Or Proteins (AREA)
Description
本発明は、メラニン凝集ホルモン受容体拮抗用組成物に関する。さらに詳しくは、本発明は、環状ジペプチド又はその塩を有効成分として含むメラニン凝集ホルモン受容体拮抗用組成物、メラニン凝集ホルモンのその受容体への結合を阻害するための環状ジペプチド又はその塩の使用、及びメラニン凝集ホルモンのその受容体への結合を阻害する方法に関する。 The present invention relates to a melanin-concentrating hormone receptor antagonistic composition. More specifically, the present invention relates to a melanin-concentrating hormone receptor antagonistic composition containing a cyclic dipeptide or a salt thereof as an active ingredient, and the use of the cyclic dipeptide or a salt thereof for inhibiting the binding of melanin-concentrating hormone to its receptor. And a method of inhibiting the binding of melanin-concentrating hormone to its receptor.
肥満は高脂肪食の摂取量の増加に伴って生じる症状であるが、糖尿病、高脂血症、高血圧、動脈硬化等の内分泌代謝異常を高率に引き起こすことから、現代社会における重大な問題の一つとされている。肥満の発症にはこれまでニューロペプチドＹやレプチン等のペプチドホルモン（Melanin Concentrating Hormone：MCH）が関与することが指摘されているが、その中で現在ではメラニン凝集ホルモンの関与が注目されている。 Obesity is a symptom that occurs with an increase in the intake of high-fat foods, but since it causes endocrine metabolism disorders such as diabetes, hyperlipidemia, hypertension, and arteriosclerosis at a high rate, it is a serious problem in modern society. It is supposed to be one. It has been pointed out that peptide hormones (Melanin Concentrating Hormone: MCH) such as neuropeptide Y and leptin are involved in the onset of obesity, and among them, the involvement of melanin-concentrating hormone is now drawing attention.
メラニン凝集ホルモン（ＭＣＨ）は１９アミノ酸からなる環状神経ペプチドであり、哺乳類では主に視床下部に発現している。ＭＣＨと肥満との関係については、例えば非特許文献１において、ＭＣＨ欠損マウスの表現型解析から当該マウスが食餌摂取の減少などによってやせを来すことが報告されている。 Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids, which is mainly expressed in the hypothalamus in mammals. Regarding the relationship between MCH and obesity, for example, in Non-Patent Document 1, it has been reported from the phenotypic analysis of MCH-deficient mice that the mice lose weight due to a decrease in food intake.
また特許文献１では、そこに開示された肥満の予防又は治療剤が、ＮＰＹ受容体又はＭＣＨ受容体拮抗作用を有しており、様々な摂食障害（特に、摂食中枢の亢進又は満腹中枢の抑制（不機能）等による食欲の異常亢進）を改善し、それに伴う肥満の防止や肥満状態の改善、或いは肥満に関連した疾病の予防や治療に有効であることが示されている。さらに当該特許文献では、その肥満の予防又は治療剤が、様々なストレス性疾患時に認められる過食の予防や治療にも有望であることが述べられている。 Further, in Patent Document 1, the preventive or therapeutic agent for obesity disclosed therein has an NPY receptor or MCH receptor antagonistic action, and is associated with various eating disorders (especially, enhancement of feeding center or satiety center). It has been shown to be effective for the prevention of obesity, the improvement of obesity associated therewith, or the prevention and treatment of diseases related to obesity by improving the suppression of appetite (abnormal increase in appetite) due to inhibition (infunction). Further, in the patent document, it is stated that the prophylactic or therapeutic agent for obesity is also promising for the prevention and treatment of overeating observed in various stress diseases.
このようにＭＣＨと肥満との関係は現在注目を浴びており、抗肥満に対応可能な効果的な薬剤の開発が強く望まれている。中でも、ヒトが摂取する観点から副作用が少ない薬剤が望ましく、更には製剤化における利便性や体内への吸収性にも優れたものが望ましいと考えられる。 Thus, the relationship between MCH and obesity is currently drawing attention, and there is a strong demand for the development of effective drugs that can cope with anti-obesity. Among them, from the viewpoint of human intake, a drug with few side effects is desirable, and further, a drug which is convenient in formulation and excellent in absorbability into the body is considered desirable.
本発明の課題は、メラニン凝集ホルモン受容体拮抗用組成物を提供することにある。また、本発明の課題は、メラニン凝集ホルモンのその受容体への結合を阻害するための当該組成物の使用、及びメラニン凝集ホルモンのその受容体への結合を阻害する方法等を提供することにある。 An object of the present invention is to provide a composition for melanin-concentrating hormone receptor antagonism. Another object of the present invention is to provide use of the 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. is there.
本発明者らは、上記課題について鋭意検討した結果、特定の環状ジペプチド又はその塩が顕著なメラニン凝集ホルモン受容体拮抗作用を有することを見出した。かかる知見に基づき、本発明者らは本発明を完成するに至った。 As a result of intensive studies on the above problems, the present inventors have found that a specific cyclic dipeptide or a salt thereof has a remarkable melanin-concentrating hormone receptor antagonistic action. Based on such knowledge, the present inventors have completed the present invention.
即ち、本発明は以下に関するが、これらに限定されない。
（１）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として含有するメラニン凝集ホルモン受容体拮抗用組成物であって、
前記環状ジペプチド又はその塩が、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記メラニン凝集ホルモン受容体拮抗用組成物。
（２）抗肥満用、肥満に関連した疾患の予防若しくは治療用、代謝亢進用、摂食障害改善用、又は食欲抑制用である、（１）に記載のメラニン凝集ホルモン受容体拮抗用組成物。
（３）環状ジペプチド又はその塩が、動植物由来ペプチドから得られるものである、（１）又は（２）に記載のメラニン凝集ホルモン受容体拮抗用組成物。
（４）メラニン凝集ホルモン受容体拮抗作用により発揮される機能の表示を付した、（１）〜（３）のいずれかに記載のメラニン凝集ホルモン受容体拮抗用組成物。
（５）機能の表示が、「肥満を予防する」、「肥満を改善する」、「体重の増加を抑制する」、「体脂肪の蓄積を抑制する」、「内臓脂肪の蓄積を抑制する」、「体内エネルギー消費量を増大させる」、「体内の脂肪の分解を促進させる」、「脂肪を消費しやすくする」、「脂肪の燃焼を促進する」、「摂食障害を改善する」、「食欲を抑制する」、「代謝を亢進する」、及び「食事の摂取を抑える」からなる群から選択される、（４）に記載のメラニン凝集ホルモン受容体拮抗用組成物。
（６）前記組成物が剤である、（１）〜（５）のいずれかに記載のメラニン凝集ホルモン受容体拮抗用組成物。
（７）メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害するための、アミノ酸を構成単位とする環状ジペプチド又はその塩の使用であって、
前記環状ジペプチド又はその塩が、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記使用。
（８）アミノ酸を構成単位とする環状ジペプチド又はその塩を有効成分として使用する、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法であって、
前記環状ジペプチド又はその塩が、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記方法。That is, the invention relates to, but is not limited to:
(1) A melanin-concentrating hormone receptor antagonistic composition comprising a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl Leucine (Cyclo (Ala-Leu)], cycloaspartyl serine (Cyclo (Asp-Ser)), cyclolysyl tyrosine (Cyclo (Lys-Tyr)), cycloarginyl aspartic acid (Cyclo (Arg-Asp)), cyclo Leucyl phenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysyl phenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], Cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)] , Cycloglycyrrhizin [Cycl o (Gly-Lys)] and cycloalanylvaline [Cyclo (Ala-Val)], and the composition for antagonizing melanin-concentrating hormone receptor, which comprises one or more selected from the group consisting of:
(2) A composition for melanin-concentrating hormone receptor antagonism according to (1), which is for anti-obesity, for preventing or treating obesity-related diseases, for enhancing metabolism, for improving eating disorders, or for suppressing appetite. .
(3) The composition for melanin-concentrating hormone receptor antagonism according to (1) or (2), wherein the cyclic dipeptide or a salt thereof is obtained from an animal- or plant-derived peptide.
(4) The melanin-concentrating hormone receptor antagonizing composition according to any one of (1) to (3), which is labeled with a function exerted by melanin-concentrating hormone receptor antagonism.
(5) Function indications "prevent obesity", "improve obesity", "suppress weight gain", "suppress body fat accumulation", "suppress visceral fat accumulation" , "Increase energy consumption in the body", "promote the breakdown of fat in the body", "make fat easy to consume", "promote fat burning", "improve eating disorders", " The composition for melanin-concentrating hormone receptor antagonism according to (4), which is selected from the group consisting of "suppressing appetite", "enhancing metabolism", and "suppressing food intake".
(6) The melanin-concentrating hormone receptor antagonistic composition according to any one of (1) to (5), wherein the composition is an agent.
(7) Use of a cyclic dipeptide having an amino acid as a structural unit or a salt thereof for inhibiting the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor,
The cyclic dipeptide or a salt thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl Leucine (Cyclo (Ala-Leu)], cycloaspartyl serine (Cyclo (Asp-Ser)), cyclolysyl tyrosine (Cyclo (Lys-Tyr)), cycloarginyl aspartic acid (Cyclo (Arg-Asp)), cyclo Leucyl phenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysyl phenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], Cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)] , Cycloglycyrrhizin [Cycl o (Gly-Lys)], and cycloalanylvaline [Cyclo (Ala-Val)], or one or more selected from the group.
(8) A method for inhibiting the binding of a melanin-concentrating hormone to a melanin-concentrating hormone receptor, which comprises using a cyclic dipeptide having an amino acid as a structural unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl Leucine (Cyclo (Ala-Leu)], cycloaspartyl serine (Cyclo (Asp-Ser)), cyclolysyl tyrosine (Cyclo (Lys-Tyr)), cycloarginyl aspartic acid (Cyclo (Arg-Asp)), cyclo Leucylphenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], Cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)] , Cycloglycyrrhizin [Cycl o (Gly-Lys)], and cycloalanilvaline [Cyclo (Ala-Val)], or one or more selected from the group consisting of the above.
本発明によって、優れたメラニン凝集ホルモン受容体拮抗作用を有する組成物を提供することができる。本発明のメラニン凝集ホルモン受容体拮抗用組成物を任意の投与方法において使用することで、抗肥満、肥満に関連した疾患の予防若しくは治療、代謝亢進、摂食障害の改善、又は食欲抑制等の効果を得ることができる。 The present invention can provide a composition having an excellent melanin-concentrating hormone receptor antagonistic action. By using the composition for melanin-concentrating hormone receptor antagonism of the present invention in any method of administration, anti-obesity, prevention or treatment of obesity-related diseases, hypermetabolism, improvement of eating disorders, or suppression of appetite, etc. The effect can be obtained.
１．メラニン凝集ホルモン及びメラニン凝集ホルモン受容体拮抗作用
本明細書において「メラニン凝集ホルモン」は、哺乳類の視床下部に多く発現する１９アミノ酸からなる環状神経ペプチドであり、その名称（Melanin Concentrating Hormone）からＭＣＨとも称される。また、本明細書において「メラニン凝集ホルモン受容体拮抗作用」とは、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合に拮抗（競合）してそのメラニン凝集ホルモンの結合を阻害する作用を意味し、そのような拮抗作用を有する組成物を「メラニン凝集ホルモン受容体拮抗用組成物」という。メラニン凝集ホルモンの受容体には２種類のサブタイプが存在しており、それぞれ１型受容体（ＭＣＨ１Ｒ）及び２型受容体（ＭＣＨ２Ｒ）と称される。本発明におけるメラニン凝集ホルモン受容体にはいずれのサブタイプも含まれるが、好ましくは１型受容体（ＭＣＨ１Ｒ）である。 1. Melanin-concentrating hormone and melanin-concentrating hormone receptor antagonism In the present specification, "melanin-concentrating hormone" is a cyclic neuropeptide consisting of 19 amino acids that is highly expressed in the hypothalamus of mammals, and is also called MCH from its name (Melanin Concentrating Hormone). Is called. In the present specification, the term “melanin-concentrating hormone receptor antagonistic action” means an action of antagonizing (competing) the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor to inhibit the binding of the melanin-concentrating hormone. A composition having such an antagonistic effect is referred to as a "melanin-concentrating hormone receptor antagonistic composition". There are two subtypes of melanin-concentrating hormone receptors, which are called type 1 receptor (MCH1R) and type 2 receptor (MCH2R), respectively. The melanin-concentrating hormone receptor in the present invention includes any subtype, but is preferably the type 1 receptor (MCH1R).
メラニン凝集ホルモン受容体拮抗作用は、公知の方法に従って評価することができる。例えば、メラニン凝集ホルモン受容体を発現した細胞を用いて、メラニン凝集ホルモンを添加したときの細胞内カルシウムイオン濃度の変化を測定し、試料が存在する場合と存在しない場合との測定値を比較して評価することができる。より具体的には、試料が存在しない場合の測定値に対して試料が存在する測定値の方が低い（即ち、細胞内カルシウムイオン濃度の変化が小さい）ほど、メラニン凝集ホルモン受容体拮抗作用は大きいと評価することができる。 The melanin-concentrating hormone receptor antagonism can be evaluated according to a known method. For example, using cells expressing the melanin-concentrating hormone receptor, the change in intracellular calcium ion concentration when the melanin-concentrating hormone was added was measured, and the measured values in the presence and absence of the sample were compared. Can be evaluated. More specifically, the lower the measured value in the presence of the sample (that is, the smaller the change in intracellular calcium ion concentration) is, the more the melanin-concentrating hormone receptor antagonism is compared with the measured value in the absence of the sample. It can be evaluated as large.
２．環状ジペプチド
本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、アミノ酸のアミノ基とカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する環状ジペプチドのことをいう。そのため、環状ジペプチドは、鎖状のジペプチドとは区別される。なお、本明細書において、環状ジペプチド又はその塩をまとめて、単に、環状ジペプチドと称する場合がある。また、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わず、例えば、〔Cyclo(Met-Arg)〕と〔Cyclo(Arg-Met)〕とは同じ環状ジペプチドを表すものである。 2. Cyclic dipeptide In the present specification, the term "cyclic dipeptide" refers to a cyclic dipeptide having a diketopiperazine structure produced by dehydration condensation of an amino group and a carboxyl group of an amino acid, which is characterized by having an amino acid as a constitutional unit. Say. Therefore, cyclic dipeptides are distinguished from linear dipeptides. In addition, in this specification, a cyclic dipeptide or a salt thereof may be collectively referred to simply as a cyclic dipeptide. Further, in the present specification, if the amino acid constitution of the cyclic dipeptide is the same, the order in which they are described may be any, for example, [Cyclo (Met-Arg)] and [Cyclo (Arg-Met)] Represent the same cyclic dipeptide.
環状ジペプチドではアミド結合を介して二個のアミノ酸の末端部分が結合しているため（即ち、環状ジペプチドは、アミノ末端とカルボキシ末端とがアミド結合することによって形成される環状構造を有しているため）、分子末端部分に極性基であるカルボキシル基やアミノ基が露出している直鎖状ジペプチド（特に、同種のアミノ酸組成からなる直鎖状ジペプチド）と比較して環状ジペプチドは脂溶性が高いという特徴を有する。そのため、環状ジペプチドは直鎖状のジペプチドと比較して、消化管透過性や膜透過性に優れる。このことは、過去に報告されているラット反転腸管を用いた化合物透過試験の結果からも明らかである（J. Pharmacol, 1998, 50: 167-172）。また環状ジペプチドは、その特異的な構造から各種ペプチダーゼに対する耐性も高まると考えられる。 In a cyclic dipeptide, the terminal portions of two amino acids are linked via an amide bond (that is, the cyclic dipeptide has a cyclic structure formed by an amide bond between the amino terminus and the carboxy terminus). Because of this, cyclic dipeptides are more lipophilic than linear dipeptides in which the carboxyl group or amino group, which is a polar group, is exposed at the end of the molecule (especially linear dipeptides of the same amino acid composition) It has the feature. Therefore, the cyclic dipeptide is superior to the digestive tract permeability and the membrane permeability as compared with the linear dipeptide. This is also clear from the results of the compound permeation test using rat everted intestine reported in the past (J. Pharmacol, 1998, 50: 167-172). Further, it is considered that the cyclic dipeptide has increased resistance to various peptidases due to its specific structure.
本発明において有効成分として含有される環状ジペプチド又はその塩は、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上のものである。環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される３つ以上を有効成分とすることが好ましい。また、前記環状ジペプチド又はその塩の中では、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、及びシクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、及びシクロロイシルリシン〔Cyclo(Leu-Lys)〕からなる群から選択される１つ又は２つ以上がより好ましい。 The cyclic dipeptide or a salt thereof contained as an active ingredient in the present invention includes cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu) -Lys)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloleucyl phenylalanine [Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysyl phenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [ Cyclo (Gln-Leu)], cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine (Cyclo ( Lys-Ser)], cycloglycyl lysine [Cyclo (Gly-Lys)], and cycloalanylvaline [Cyclo (Ala-Val)], or two or more thereof. The number of cyclic dipeptides or salts thereof is not particularly limited, but in the present invention, it is preferable to use three or more selected from the above-mentioned cyclic dipeptides or salts thereof as active ingredients. Further, in the cyclic dipeptide or a salt thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cyclolysyl serine [Cyclo (Lys-Ser)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], Cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)] , Cycloarginyl aspartic acid [Cyclo (Arg-Asp)], and cycloleucylphenylalanine [Cyclo (Leu-Phe)], and one or more selected from the group consisting of cycloarginyl leucine [Cyclo (Arg-Leu)], cyclolysyl serine [Cyclo (Lys-Ser)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], and cycloleucyl lysine [Cyclo (Leu-Lys)]. More preferably, one or two or more of the
本明細書において「環状ジペプチドの塩」とは、前記環状ジペプチドの薬理学的に許容される任意の塩（無機塩及び有機塩を含む）をいい、例えば、前記環状ジペプチドのナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩、アンモニウム塩、塩酸塩、硫酸塩、硝酸塩、燐酸塩、有機酸塩（酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩、蟻酸塩、安息香酸塩、ピクリン酸塩、ベンゼンスルホン酸塩、トリフルオロ酢酸塩等）等が挙げられるが、これらに限定されない。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。 In the present specification, the “salt of a cyclic dipeptide” refers to any pharmacologically acceptable salt of the above cyclic dipeptide (including an inorganic salt and an organic salt), for example, a sodium salt or a potassium salt of the above cyclic dipeptide. , Calcium salt, magnesium salt, ammonium salt, hydrochloride, sulfate, nitrate, phosphate, organic acid salt (acetate, citrate, maleate, malate, oxalate, lactate, succinate) , Fumarate, propionate, formate, benzoate, picrate, benzenesulfonate, trifluoroacetate, etc.) and the like, but are not limited thereto. Salts of cyclic dipeptides can be readily prepared by those of skill in the art by any method known in the art.
本発明で用いる環状ジペプチドは、当該分野で公知の方法に従って調製することができる。例えば、化学合成法や酵素法、微生物発酵法により製造されてもよく、直鎖状ペプチドを脱水及び環化させることにより合成されてもよく、特開２００３−２５２８９６号公報やJournal of Peptide Science, 10, 737-737, 2004に記載の方法に従って調製することもできる。例えば、動植物由来タンパク質を含む原料に酵素処理や熱処理を施して得られる動植物由来ペプチドを、さらに高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。これらの点から、本発明で用いる環状ジペプチド又はその塩は、化学的又は生物的に合成されるものであってもよいし、或いは動植物由来ペプチドから得られるものであってもよい。 The cyclic dipeptide used in the present invention can be prepared according to a method known in the art. For example, it may be produced by a chemical synthesis method, an enzymatic method, a microbial fermentation method, or may be synthesized by dehydrating and cyclizing a linear peptide, and is disclosed in JP-A-2003-252896 and Journal of Peptide Science, It can also be prepared according to the method described in 10, 737-737, 2004. For example, a heat-treated animal- or plant-derived peptide rich in cyclic dipeptides can be obtained by subjecting an animal- or plant-derived peptide obtained by subjecting a raw material containing an animal or plant-derived protein to enzyme treatment or heat treatment, to high-temperature heat treatment. From these points, the cyclic dipeptide or a salt thereof used in the present invention may be chemically or biologically synthesized, or may be obtained from an animal or plant derived peptide.
３．動植物由来ペプチド
本明細書における「動植物由来ペプチド」は特に限定されないが、例えば、大豆ペプチド、茶ペプチド、麦芽ペプチド、乳ペプチド、プラセンタペプチド、コラーゲンペプチド等を用いることができる。これらのうち、本発明では大豆ペプチド及び茶ペプチドが好ましい。動植物由来ペプチドは、動植物由来のタンパク質又はタンパク質を含む原料から調製したものを用いてもよく、或いは市販品を用いてもよい。 3. Animal- and plant-derived peptide The "animal- and plant-derived peptide" in the present specification is not particularly limited, and for example, soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, collagen peptide and the like can be used. Of these, soybean peptides and tea peptides are preferred in the present invention. As the animal- and plant-derived peptide, one prepared from a protein or animal-derived protein or a raw material containing the protein may be used, or a commercially available product may be used.
３−１．大豆ペプチド
本明細書でいう「大豆ペプチド」とは、大豆タンパク質に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる低分子ペプチドをいう。原料となる大豆（学名：Glycine max）は品種や産地などの制限なく用いることができ、粉砕品などの加工品段階のものを用いることもできる。 3-1. Soybean peptide The term “soybean peptide” used herein refers to a low molecular weight peptide obtained by subjecting soybean protein to enzymatic treatment or heat treatment to reduce the molecular weight of the protein. The soybean (scientific name: Glycine max) used as a raw material can be used without limitation on the variety and the production area, and a processed product such as a crushed product can also be used.
３−２．茶ペプチド
本明細書でいう「茶ペプチド」とは、茶（茶葉や茶殻を含む）抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる茶由来の低分子ペプチドをいう。抽出原料となる茶葉としては、茶樹（学名：Camellia sinensis）を用いて製造された茶葉の葉、茎など、抽出して飲用可能な部位を使用することができる。また、その形態も大葉、粉状など制限されない。茶葉の収穫期についても、所望する香味に合わせて適宜選択できる。 3-2. Tea peptide The term "tea peptide" used herein refers to a tea-derived low-molecular peptide obtained by subjecting a tea (including tea leaves and tea leaves) extract to an enzyme treatment or a heat treatment to reduce the protein into a low-molecular weight protein. . As the tea leaf used as an extraction raw material, a leaf, stem or the like of a tea leaf produced by using a tea tree (scientific name: Camellia sinensis) can be used as an extractable and drinkable portion. Also, the form is not limited to large leaves or powder. The harvest time of tea leaves can also be appropriately selected according to the desired flavor.
３−３．麦芽ペプチド
本明細書でいう「麦芽ペプチド」とは、麦芽又はその粉砕物から得られる抽出物に酵素処理や熱処理を施し、タンパク質を低分子化することによって得られる麦芽由来の低分子ペプチドをいう。原料となる麦芽ペプチドは、品種や産地などの制限なく用いることができるが、特に大麦の種子を発芽させた大麦麦芽が好適に用いられる。なお、本明細書では大麦麦芽のことを単に麦芽と表記することもある。 3-3. Malt Peptide The term "malt peptide" as used herein refers to a malt-derived low-molecular peptide obtained by subjecting an extract obtained from malt or a crushed product thereof to enzymatic treatment or heat treatment to reduce the protein molecular weight. . The malt peptide used as a raw material can be used without limitation on the variety, the production area, etc. In particular, barley malt obtained by germinating barley seeds is preferably used. In the present specification, barley malt may be simply referred to as malt.
３−４．乳ペプチド
本明細書でいう「乳ペプチド」とは、天然の乳由来の成分である乳蛋白質をアミノ酸が少なくとも数個結合した分子に分解したものである。より具体的には、ホエイ（乳清タンパク質）又はカゼイン等の乳蛋白質をプロテナーゼ等の酵素により加水分解し、これを濾過して得られる濾液を殺菌及び／又は濃縮して乾燥することにより得られるホエイペプチド、カゼインペプチド等が挙げられる。 3-4. Milk Peptide The term “milk peptide” as used herein is obtained by decomposing a milk protein, which is a natural milk-derived component, into a molecule having at least several amino acids bound thereto. More specifically, it is obtained by hydrolyzing a milk protein such as whey (whey protein) or casein with an enzyme such as proteinase, filtering the filtrate, and sterilizing and / or concentrating and drying the filtrate. Examples thereof include whey peptide and casein peptide.
３−５．プラセンタペプチド
プラセンタとは哺乳類の胎盤のことであり、その優れた機能性から、近年、健康食品、化粧品、医薬品素材として用いられている。本明細書において「プラセンタペプチド」とは、プラセンタを酵素処理、又は亜臨界処理により可溶化、低分子化したものをいう。また、本来の意味とは異なるが、植物の胎座から得られる抽出物が胎盤由来のプラセンタと同等の生理学的効果を有するものとして健康食品、化粧品等に利用されており、これらは植物プラセンタと呼ばれる。本明細書における「プラセンタペプチド」には、植物プラセンタに酵素処理、又は亜臨界処理等を施し、可溶化、低分子化したものも含まれる。 3-5. Placenta Peptide Placenta is the placenta of mammals, and due to its excellent functionality, it has recently been used as a health food, cosmetics, and pharmaceutical material. In the present specification, the “placenta peptide” refers to a placenta that has been solubilized and reduced in molecular weight by enzyme treatment or subcritical treatment. Further, although different from the original meaning, an extract obtained from the placenta of a plant is used in health foods, cosmetics, etc. as having a physiological effect equivalent to placenta-derived placenta, and these are be called. The “placenta peptide” in the present specification also includes those obtained by subjecting plant placenta to enzyme treatment, subcritical treatment, or the like to solubilize or reduce the molecular weight thereof.
３−６．コラーゲンペプチド
本明細書でいう「コラーゲンペプチド」とは、コラーゲン又はその粉砕物を酵素処理や熱処理を施し、コラーゲンを低分子化することによって得られる低分子ペプチドをいう。コラーゲンは動物の結合組織の主要なタンパク質であり、ヒトを含めた哺乳類の身体に最も大量に含まれるタンパク質である。 3-6. Collagen peptide The term "collagen peptide" as used herein refers to a low molecular weight peptide obtained by subjecting collagen or a pulverized product thereof to an enzymatic treatment or a heat treatment to lower the molecular weight of collagen. Collagen is a major protein in connective tissue of animals and is the most abundant protein in the body of mammals including humans.
４．動植物由来ペプチド熱処理物
上述した通り、動植物由来ペプチドを高温加熱処理することで、環状ジペプチドを豊富に含む動植物由来ペプチド熱処理物を得ることができる。本明細書において「高温加熱処理」とは、１００℃以上の温度かつ大気圧を超える圧力下で一定時間処理することを意味する。高温高圧処理装置としては、耐圧性抽出装置や圧力鍋、オートクレーブなどを条件に合わせて用いることができる。 4. Heat-treated product of animal- and plant-derived peptide As described above, heat-treated animal- and plant-derived peptide at a high temperature can give a heat-treated product of animal- and plant-derived peptide rich in cyclic dipeptides. In the present specification, “high temperature heat treatment” means treatment at a temperature of 100 ° C. or higher and a pressure exceeding atmospheric pressure for a certain period of time. As the high-temperature and high-pressure treatment device, a pressure-resistant extraction device, a pressure cooker, an autoclave, etc. can be used according to the conditions.
高温加熱処理における温度は、１００℃以上である限り特に限定されないが、好ましくは１００℃〜１７０℃、より好ましくは１１０℃〜１５０℃、さらにより好ましくは１２０℃〜１４０℃である。なお、この温度は、加熱装置として耐圧性抽出装置を用いた場合には抽出カラムの出口温度を測定した値を示し、加熱装置としてオートクレーブを用いた場合には、圧力容器内の中心温度の温度を測定した値を示す。 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, and still more preferably 120 ° C to 140 ° C. Note that this temperature indicates a value obtained by measuring the outlet temperature of the extraction column when a pressure-resistant extraction device is used as the heating device, and when an autoclave is used as the heating device, the temperature of the central temperature in the pressure vessel. The measured value is shown.
高温加熱処理における圧力は、大気圧を超える圧力である限り特に限定されないが、好ましくは０．１０１ＭＰａ〜０．７９ＭＰａ、より好ましくは０．１０１ＭＰａ〜０．６０ＭＰａ、さらにより好ましくは０．１０１ＭＰａ〜０．４８ＭＰａである。 The pressure in the high temperature heat treatment is not particularly limited as long as it is a pressure higher than 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. It is 0.48 MPa.
高温加熱処理時間は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは１５分〜６００分程度、より好ましくは３０分〜５００分程度、さらにより好ましくは６０分〜３００分程度である。 The high-temperature heat treatment time is not particularly limited as long as a treated product containing a cyclic dipeptide is obtained, but is preferably about 15 minutes to 600 minutes, more preferably about 30 minutes to 500 minutes, and even more preferably about 60 minutes to 300 minutes. Is.
また、動植物由来ペプチドの高温加熱処理条件は、環状ジペプチドを含む処理物が得られる限り特に限定されないが、好ましくは［温度：圧力：時間］が［１００℃〜１７０℃：０．１０１ＭＰａ〜０．７９ＭＰａ：１５分〜６００分］、より好ましくは［１１０℃〜１５０℃：０．１０１ＭＰａ〜０．６０ＭＰａ：３０分〜５００分］、さらにより好ましくは［１２０℃〜１４０℃：０．１０１ＭＰａ〜０．４８ＭＰａ：６０分〜３００分］である。 Further, the high temperature heat treatment condition of the animal and plant derived peptide is not particularly limited as long as a treated product containing a cyclic dipeptide is obtained, but [temperature: pressure: time] is preferably [100 ° C to 170 ° C: 0.101 MPa to 0. 79 MPa: 15 minutes to 600 minutes], more preferably [110 ° C. to 150 ° C .: 0.101 MPa to 0.60 MPa: 30 minutes to 500 minutes], even more preferably [120 ° C. to 140 ° C .: 0.101 MPa to 0]. .48 MPa: 60 minutes to 300 minutes].
なお、得られた動植物由来ペプチド熱処理物に対して、所望により、濾過、遠心分離、濃縮、限外濾過、凍結乾燥、粉末化等の処理を行ってもよい。また、動植物由来ペプチド熱処理物中の特定の環状ジペプチドが所望の含有量に満たなければ、不足する特定の環状ジペプチドについては他の動植物由来ペプチドや市販品、合成品を用いて適宜追加することもできる。 The obtained heat-treated animal- and plant-derived peptides may be subjected to treatments such as filtration, centrifugation, concentration, ultrafiltration, freeze-drying, and pulverization, if desired. Further, if the specific cyclic dipeptide in the heat-treated product of animal or plant-derived peptides does not meet the desired content, other specific animal- or plant-derived peptides or commercially available products for the lacking specific cyclic dipeptide may be appropriately added. it can.
５．メラニン凝集ホルモン受容体拮抗用組成物
５−１．環状ジペプチド含有メラニン凝集ホルモン受容体拮抗用組成物
本発明の一態様は、特定の環状ジペプチド又はその塩を有効成分として含むメラニン凝集ホルモン受容体拮抗用組成物である。 5. Composition for antagonisting melanin-concentrating hormone receptor
5-1. Cyclic dipeptide-containing melanin-concentrating hormone receptor antagonistic composition One aspect of the present invention is a melanin-concentrating hormone receptor antagonistic composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient.
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として含むものである。本発明のメラニン凝集ホルモン受容体拮抗用組成物に含まれる環状ジペプチド又はその塩の数は特に限定されないが、本発明では、上述した環状ジペプチド又はその塩から選択される３つ以上が含まれることが好ましい。前記環状ジペプチド又はその塩の中では、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、及びシクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕からなる群から選択される１つ又は２つ以上が好ましく、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、及びシクロロイシルリシン〔Cyclo(Leu-Lys)〕からなる群から選択される１つ又は２つ以上がより好ましい。 The melanin-concentrating hormone receptor antagonistic composition of the present invention, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys- )], Cycloalanyl leucine [Cyclo (Ala-Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo (Arg -Asp)], cycloleucyl phenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine (Cyclo (Gln-Ser)), cyclolysyl phenylalanine (Cyclo (Lys-Phe)), cycloglutaminyl leucine (Cyclo (Lys-Phe)) Gln-Leu)], cycloalanylphenylalanine (Cyclo (Ala-Phe)), cycloarginylphenylalanine (Cyclo (Arg-Phe)], cycloarginyltyrosine (Cyclo (Arg-Tyr)), cyclolysylserine (Cyclo (Lys-Ser)], cyclo Rishirurishin [Cyclo (Gly-Lys)], and is intended to include one or more cyclic dipeptide or a salt thereof is selected from the group consisting of cycloalkyl alanyl-valine [Cyclo (Ala-Val)] as an active ingredient. The number of cyclic dipeptides or salts thereof contained in the melanin-concentrating hormone receptor antagonistic composition of the present invention is not particularly limited, but in the present invention, three or more selected from the above-mentioned cyclic dipeptides or salts thereof are contained. Is preferred. Among the cyclic dipeptides or salts thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cyclolysyl serine [Cyclo (Lys-Ser)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloroyl Sillycine (Cyclo (Leu-Lys)], cycloalanyl leucine (Cyclo (Ala-Leu)), cycloaspartyl serine (Cyclo (Asp-Ser)), cyclolysyl tyrosine (Cyclo (Lys-Tyr)), cyclo One or more selected from the group consisting of arginyl aspartic acid [Cyclo (Arg-Asp)] and cycloleucylphenylalanine [Cyclo (Leu-Phe)] is preferable, and cycloarginyl leucine [Cyclo (Arg-Arg) -Leu)], cyclolysyl serine [Cyclo (Lys-Ser)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], and cycloleucyl lysine [Cyclo (Leu-Lys)]. One or two or more are more preferable.
本発明のメラニン凝集ホルモン受容体拮抗用組成物における環状ジペプチド又はその塩の含有量は、その投与形態、投与方法などを考慮し、本発明の所望の効果が得られるような量であればよく、特に限定されるものではない。例えば、大豆ペプチド、茶ペプチド、麦芽ペプチド、乳ペプチド、プラセンタペプチド、又はコラーゲンペプチドを原料として用いる場合、本発明の組成物における環状ジペプチド又はその塩の含有量の総量は、２００ｐｐｍ／Ｂｒｉｘ以上、好ましくは３００ｐｐｍ／Ｂｒｉｘ以上であり、５０００ｐｐｍ／Ｂｒｉｘ以下、好ましくは４０００ｐｐｍ／Ｂｒｉｘ以下であり、典型的には、２００〜５０００ｐｐｍ／Ｂｒｉｘ、好ましくは３００〜４０００ｐｐｍ／Ｂｒｉｘである。また、本発明のメラニン凝集ホルモン受容体拮抗用組成物におけるシクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、シクロアラニルバリン〔Cyclo(Ala-Val)〕、又はそれぞれに対応する塩の含有量としては、１．０ｐｐｍ／Ｂｒｉｘ以上、好ましくは３．０ｐｐｍ／Ｂｒｉｘ以上であり、３０００ｐｐｍ／Ｂｒｉｘ以下、好ましくは２０００ｐｐｍ／Ｂｒｉｘ以下であり、典型的には、１．０〜３０００ｐｐｍ／Ｂｒｉｘ、好ましくは３．０〜２０００ｐｐｍ／Ｂｒｉｘである。本発明において、環状ジペプチド又はその塩の含有量は上記の通りＢｒｉｘ（ブリックス：Ｂｘ）あたりの量で表される。本明細書において「Ｂｒｉｘあたりの量」は、２０℃のショ糖溶液（ショ糖のみを溶質として含む水溶液）の質量百分率に相当する値で定められる量を意味する。なお、特に断りがない限り、本明細書において用いる「ｐｐｍ」は、重量／容量（ｗ／ｖ）のｐｐｍを意味し、１．０ｐｐｍ／Ｂｒｉｘは溶媒の比重が１の場合、０．１ｍｇ／ｍＬと換算され、０．０１重量％と換算されるものである。 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 such that the desired effect of the present invention can be obtained in consideration of its administration form, administration method and the like. It is not particularly limited. For example, when soybean peptide, tea peptide, malt peptide, milk peptide, placenta peptide, or collagen peptide is used as a raw material, the total content of the cyclic dipeptide or its salt in the composition of the present invention is 200 ppm / Brix or more, preferably Is 300 ppm / Brix or more and 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, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu- Lys)], cycloalanyl leucine [Cyclo (Ala-Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo ( Arg-Asp)], cycloleucyl phenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine (Cyclo (Gln-Ser)), cyclolysyl phenylalanine (Cyclo (Lys-Phe)), cycloglutaminyl leucine (Cyclo (Gln-Leu)], cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [ Cyclo (Lys-Ser) , Cycloglycyrrhizin [Cyclo (Gly-Lys)], cycloalanylvaline [Cyclo (Ala-Val)], or a salt corresponding to each, 1.0 ppm / Brix or more, preferably 3. It is 0 ppm / Brix or more and 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 the salt thereof is represented by the amount per Brix (Brix: Bx) as described above. In the present specification, “amount per Brix” means an amount determined by a value corresponding to a mass percentage of a sucrose solution (aqueous solution containing only sucrose as a solute) at 20 ° C. Unless otherwise specified, “ppm” used in the present specification means ppm of weight / volume (w / v), and 1.0 ppm / Brix means 0.1 mg / in the case where the specific gravity of the solvent is 1. It is converted into mL and converted into 0.01% by weight.
環状ジペプチド又はその塩の含有量は、公知の方法に従って測定することができる。例えば、ＬＣ−ＭＳ／ＭＳ又は糖度計を用いて測定することができる。 The content of the cyclic dipeptide or its salt can be measured according to a known method. For example, it can be measured using LC-MS / MS or a saccharimeter.
また、本発明のメラニン凝集ホルモン受容体拮抗用組成物は、前記環状ジペプチド又はその塩の１つ又は２つ以上を含む動植物由来ペプチド熱処理物を有効成分として含むものであってもよい。そのような動植物由来ペプチド熱処理物としては、特に限定されないが、大豆ペプチド熱処理物及び茶ペプチド熱処理物が好ましい。 The composition for melanin-concentrating hormone receptor antagonism of the present invention may contain, as an active ingredient, a heat-treated animal- or plant-derived peptide containing one or more of the cyclic dipeptides or salts thereof. The heat-treated product of animal- or plant-derived peptides is not particularly limited, but a heat-treated product of soybean peptide and a heat-treated product of tea peptide are preferable.
動植物由来ペプチド熱処理物を用いた場合、本発明のメラニン凝集ホルモン受容体拮抗用組成物におけるその含有量は、その投与形態、投与方法などを考慮し、本発明の所望の効果が得られるような量であればよく、特に限定されるものではない。例えば、当該含有量は、本発明の組成物の全重量に対して０．００１重量％以上、好ましくは０．０１重量％以上、より好ましくは０．１重量％以上である。また、動植物由来ペプチド熱処理物の含有量は、本発明の組成物の全重量に対して９９重量％以下、好ましくは５０重量％以下、より好ましくは１０重量％以下である。 When a heat-treated animal-or plant-derived peptide is used, its content in the composition for melanin-concentrating hormone receptor antagonist of the present invention is such that the desired effect of the present invention can be obtained in consideration of its administration form, administration method, etc. There is no particular limitation as long as it is an amount. For example, the content is 0.001% by weight or more, preferably 0.01% by weight or more, more preferably 0.1% by weight or more based on the total weight of the composition of the present invention. The content of the heat-treated animal- and plant-derived peptides is 99% by weight or less, preferably 50% by weight or less, more preferably 10% by weight or less, based on the total weight of the composition of the present invention.
５−２．他の成分
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、その形態に応じて、上記有効成分の他に、任意の添加剤や通常用いられる任意の成分を含有することができる。これらの添加剤及び／又は成分の例としては、ビタミンＥ、ビタミンＣ等のビタミン類、ミネラル類、栄養成分、香料などの生理活性成分の他、製剤化において配合される賦形剤、結合剤、乳化剤、緊張化剤（等張化剤）、緩衝剤、溶解補助剤、防腐剤、安定化剤、抗酸化剤、着色剤、凝固剤、又はコーティング剤等が挙げられるが、これらに限定されるものではない。 5-2. Other Ingredients The melanin-concentrating hormone receptor antagonistic composition of the present invention may contain, in addition to the above-mentioned active ingredient, any additive or any commonly used ingredient, depending on its form. Examples of these additives and / or components include vitamins such as vitamin E and vitamin C, minerals, nutritional components, physiologically active components such as flavors, as well as excipients and binders to be blended in formulation. Examples include, but are not limited to, emulsifiers, tensioning agents (tonicity agents), buffers, solubilizers, preservatives, stabilizers, antioxidants, coloring agents, coagulants, or coating agents. Not something.
５−３．用途
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、上述した有効成分を含有することを特徴としており、当該有効成分がメラニン凝集ホルモン受容体のその受容体への結合に拮抗し得る。上述した通り、メラニン凝集ホルモン受容体にはＭＣＨ１Ｒ及びＭＣＨ２Ｒの２種類のサブタイプが含まれることから、本発明の組成物は、ＭＣＨ１Ｒ（ＭＣＨ１受容体）拮抗用組成物及び／又はＭＣＨ２Ｒ（ＭＣＨ２受容体）拮抗用組成物となり得る。 5-3. Use The composition for antagonizing the melanin-concentrating hormone receptor of the present invention is characterized by containing the above-mentioned active ingredient, and the active ingredient can antagonize the binding of the melanin-concentrating hormone receptor to the receptor. As described above, since the melanin-concentrating hormone receptor includes two subtypes of MCH1R and MCH2R, the composition of the present invention is a MCH1R (MCH1 receptor) antagonistic composition and / or MCH2R (MCH2 receptor). The body) can be a composition for antagonism.
本発明のメラニン凝集ホルモン受容体拮抗用組成物に含まれる前述の有効成分は、メラニン凝集ホルモンのその受容体への結合阻害を通じて抗肥満、肥満に関連した疾患の予防若しくは治療、代謝亢進、摂食障害の改善、又は食欲抑制を効果的に行うことができる。従って、本発明の組成物は、抗肥満、肥満に関連した疾患の予防若しくは治療、代謝亢進、摂食障害の改善、又は食欲抑制用のメラニン凝集ホルモン受容体拮抗用組成物である。これらの用途に基づき、本発明のメラニン凝集ホルモン受容体拮抗用組成物は、抗肥満用組成物、肥満に関連した疾患の予防若しくは治療用組成物、代謝亢進用組成物、摂食障害改善用組成物、又は食欲抑制用組成物ともなり得る。ここで、肥満に関連した疾患としては、特に限定されないが、糖尿病、高脂血症、高血圧、動脈硬化、心筋梗塞、脳梗塞、脂肪肝、変形性膝関節症等が挙げられる。また、本明細書において「予防」及び「治療」には、現在の状態をより良い状態にすることと現在の状態よりも悪い状態になることを防ぐこととの両方の概念が包含されることから、改善、回復、軽減、緩和等の用語もこれらに含まれ得る。 The aforementioned active ingredient contained in the composition for melanin-concentrating hormone receptor antagonism of the present invention is anti-obesity through the inhibition of binding of melanin-concentrating hormone to its receptor, prevention or treatment of diseases associated with obesity, hypermetabolism, intake. It is possible to effectively improve eating disorders or suppress appetite. Therefore, the composition of the present invention is a melanin-concentrating hormone receptor antagonistic composition for preventing or treating obesity, obesity-related diseases, enhancing metabolism, improving eating disorders, or suppressing appetite. Based on these applications, the composition for melanin-concentrating hormone receptor antagonism of the present invention comprises an antiobesity composition, a composition for preventing or treating obesity-related diseases, a composition for enhancing metabolism, for improving eating disorders. It can also be a composition or a composition for suppressing appetite. Here, the diseases associated with obesity include, but are not limited to, diabetes, hyperlipidemia, hypertension, arteriosclerosis, myocardial infarction, cerebral infarction, fatty liver, and knee osteoarthritis. Further, in the present specification, “prevention” and “treatment” include both the concept of making the current state better and preventing the state from becoming worse than the current state. Therefore, terms such as improvement, recovery, mitigation, and mitigation may be included in these.
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、例えば、上述した他の成分等を用いて、公知の方法に従って、錠剤、顆粒剤、散剤、粉末剤、又はカプセル剤等の固形剤や、通常液剤、懸濁剤、又は乳剤等の液剤等に製剤化することができる。これらの組成物はそのまま水等と共に服用することができる。また、容易に配合することが出来る形態（例えば、粉末形態や顆粒形態）に調製後、例えば、医薬品の原材料として用いることができる。 The melanin-concentrating hormone receptor antagonistic composition of the present invention, for example, using the above-mentioned other components and the like, according to a known method, tablets, granules, powders, solid agents such as powders, or capsules, It can be usually formulated into a liquid preparation such as a liquid preparation, a suspension, or an emulsion. These compositions can be taken as they are with water or the like. Further, it can be used, for example, as a raw material for a drug after being prepared into a form that can be easily blended (for example, a powder form or a granule form).
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、或いは当該剤を含む組成物として提供することもできる。本発明の組成物としては、医薬組成物、飲食品組成物、食品組成物、飲料組成物、化粧用組成物等が挙げられるが、これらに限定されない。食品組成物の限定的でない例として、機能性食品、健康補助食品、栄養機能食品、特別用途食品、特定保健用食品、栄養補助食品、食事療法用食品、健康食品、サプリメント、食品添加剤等が挙げられる。 The composition for melanin-concentrating hormone receptor antagonism of the present invention can be provided in the form of an agent, for example, but is not limited to this form. The agent can be provided as a composition as it is or as a composition containing the agent. Examples of the composition of the present invention include, but are not limited to, pharmaceutical compositions, food and drink compositions, food compositions, beverage compositions, cosmetic compositions and the like. Non-limiting examples of food compositions include functional foods, health supplements, nutritionally functional foods, special-purpose foods, foods for specified health uses, dietary supplements, dietary foods, health foods, supplements, food additives, etc. Can be mentioned.
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、治療的用途（医療用途）又は非治療用途（非医療用途）のいずれにも適用することができる。具体的には、医薬品、医薬部外品及び化粧料等や薬事法上はこれらに属さないが、エネルギー産生促進、体重増加抑制、臓器脂肪蓄積抑制、筋増加、筋委縮軽減、又は視神経障害の予防若しくは治療効果等を明示的又は暗示的に訴求する組成物としての使用が挙げられる。 The melanin-concentrating hormone receptor antagonistic composition of the present invention can be applied to both therapeutic use (medical use) and non-therapeutic use (non-medical use). Specifically, although it does not belong to pharmaceuticals, quasi drugs, cosmetics, etc. and the Pharmaceutical Affairs Law, it promotes energy production, suppresses weight gain, suppresses fat accumulation in organs, increases muscle, reduces muscle atrophy, or reduces optic nerve damage. Examples thereof include use as a composition that explicitly or implicitly appeals for preventive or therapeutic effects.
本発明は、別の側面では、メラニン凝集ホルモン受容体拮抗作用により発揮される機能の表示を付した、前記メラニン凝集ホルモン受容体拮抗用組成物に関する。このような表示又は機能性表示は特に限定されないが、例えば、「肥満を予防する」、「肥満を改善する」、「体重の増加を抑制する」、「体脂肪の蓄積を抑制する」、「内臓脂肪の蓄積を抑制する」、「体内エネルギー消費量を増大させる」、「体内の脂肪の分解を促進させる」、「脂肪を消費しやすくする」、「脂肪の燃焼を促進する」、「摂食障害を改善する」、「食欲を抑制する」、「代謝を亢進する」、「食事の摂取を抑える」等が挙げられ、これらと同意の記載も当該表示に含まれる。本明細書において、当該表示及び機能性表示のような表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 In another aspect, the present invention relates to the above melanin-concentrating hormone receptor antagonizing composition, which is labeled with the function exhibited by the melanin-concentrating hormone receptor antagonistic action. Such indication or functional indication is not particularly limited, but for example, “prevent obesity”, “improve obesity”, “suppress weight gain”, “suppress accumulation of body fat”, “ Suppress accumulation of visceral fat, “Increase energy consumption in the body”, “Promote fat breakdown in the body”, “Make fat easy to consume”, “Promote fat burning”, “Ingestion” Examples thereof include “improve eating disorders”, “suppress appetite”, “enhance metabolism”, “suppress dietary intake”, and the like, and the statement of consent is also included in the display. In the present specification, the indication such as the indication and the functional indication may be attached to the composition itself or may be attached to the container or the packaging of the composition.
本発明のメラニン凝集ホルモン受容体拮抗用組成物は、その形態に応じた適当な方法で摂取することができる。摂取方法は、本発明に係る環状ジペプチド又はその塩が循環血中に移行できるのであれば特に限定はない。例えば、錠剤、被覆錠剤、顆粒剤、散剤、又はカプセル剤等の経口用固形製剤、内服液剤、又はシロップ剤等の経口用液体製剤、注射剤、外用剤、坐剤、又は経皮吸収剤等の非経口用製剤などの形態とすることができるが、これらに限定されない。なお、本明細書において「摂取」とは、摂取、服用、又は飲用等の全態様を含むものとして用いられる。 The melanin-concentrating hormone receptor antagonistic composition of the present invention can be ingested by an appropriate method depending on its form. The ingestion method is not particularly limited as long as the cyclic dipeptide of the present invention or a salt thereof can be transferred into the circulating blood. For example, oral solid preparations such as tablets, coated tablets, granules, powders, and capsules, oral liquid preparations such as oral liquid preparations, syrups, injections, external preparations, suppositories, transdermal absorption preparations, etc. However, the present invention is not limited thereto. In addition, in this specification, "ingestion" is used as a thing including all aspects, such as ingestion, ingestion, or drinking.
本発明のメラニン凝集ホルモン受容体拮抗用組成物の適用量は、その形態、投与方法、使用目的及び投与対象である患者又は患獣の年齢、体重、症状によって適宜設定され、一定ではない。本発明の組成物の有効ヒト摂取量は一定ではないが、例えば、その有効成分である環状ジペプチド又はその塩の重量として、体重５０ｋｇのヒトで一日あたり、好ましくは１０ｍｇ以上、より好ましくは１００ｍｇ以上である。また、投与は所望の投与量範囲内において、１日内において単回又は数回に分けて行ってもよい。投与期間も任意である。なお、本発明の組成物の有効ヒト摂取量とは、ヒトにおいて有効な効果を示す本発明のメラニン凝集ホルモン受容体拮抗用組成物の摂取量のことをいう。 The applied amount of the melanin-concentrating hormone receptor antagonistic composition of the present invention is appropriately set depending on the form, administration method, purpose of use and age, body weight, or symptom of the patient or patient to be administered, and is not constant. Although the effective human intake of the composition of the present invention is not constant, for example, the weight of the active ingredient, cyclic dipeptide or salt thereof, is preferably 10 mg or more, more preferably 100 mg per day for a 50 kg human. That is all. In addition, the administration may be performed within a desired dose range in a single dose or in divided doses within one day. The administration period is also arbitrary. The effective human intake of the composition of the present invention refers to the intake of the melanin-concentrating hormone receptor antagonizing composition of the present invention showing an effective effect in humans.
本発明のメラニン凝集ホルモン受容体拮抗用組成物の適用対象は、好ましくはヒトであるが、ウシ、ウマ、ヤギ等の家畜動物、イヌ、ネコ、ウサギ等のペット動物、又は、マウス、ラット、モルモット、サル等の実験動物であってもよい。ヒト以外の動物を対象に投与する場合、マウス１個体当たり約２０ｇに対して１日あたりの使用量は、組成物中の有効成分の含有量、適用対象者の状態、体重、性別及び年齢等の条件により異なるが、通常、環状ジペプチド又はその塩の総配合量として、好ましくは１０ｍｇ／ｋｇ以上、より好ましくは１００ｍｇ／ｋｇ以上を摂取できる量にするとよい。 The application target of the melanin-concentrating hormone receptor antagonistic composition of the present invention is preferably human, but livestock animals such as cattle, horses, goats, pet animals such as dogs, cats, rabbits, or mice, rats, It may be an experimental animal such as a guinea pig or a monkey. When administered to animals other than humans, the daily usage amount is about 20 g per mouse, the content of the active ingredient in the composition, the condition of the subject, weight, sex and age, etc. The total amount of cyclic dipeptide or a salt thereof is preferably 10 mg / kg or more, more preferably 100 mg / kg or more, though it may vary depending on the conditions described above.
６．メラニン凝集ホルモンのその受容体への結合を阻害するための環状ジペプチド又はその塩の使用
本発明の一態様は、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩の、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害するための使用である。好ましくは、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩の、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害するための使用である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものの、メラニン凝集ホルモンのその受容体への結合を阻害するための使用である。 6. Use of Cyclic Dipeptide or Salt Thereof to Inhibit Binding of Melanin-Concentrating Hormone to Its Receptor One aspect of the present invention is a melanin-aggregating melanin-concentrating hormone of a specific cyclic dipeptide having an amino acid as a constituent unit or a salt thereof. Use to inhibit binding to hormone receptors. Preferably, cycloarginyl leucine (Cyclo (Arg-Leu)), cycloglutaminyl arginine (Cyclo (Gln-Arg)), cycloleucyl lysine (Cyclo (Leu-Lys)), cycloalanyl leucine (Cyclo (Ala -Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloleucyl phenylalanine [Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], cycloalanylphenylalanine [ Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)], cycloglycyllysine [Cyclo (Gly-Lys)], and shiku Use of one or more cyclic dipeptides selected from the group consisting of alanylvaline [Cyclo (Ala-Val)] or salts thereof for inhibiting the binding of melanin-concentrating hormone to melanin-concentrating hormone receptor . More preferred is the use of three or more selected from the above cyclic dipeptides or salts thereof, for inhibiting the binding of melanin-concentrating hormone to its receptor.
本発明の使用には、例えば、抗肥満、肥満に関連した疾患の予防若しくは治療、代謝亢進、摂食障害改善、又は食欲抑制のための、前記環状ジペプチド又はその塩の使用が含まれるが、これらに限定されるものではない。また、当該使用は、ヒト又は非ヒト動物における使用であり、治療的使用であっても非治療的使用であってもよい。ここで、「非治療的」とは、医療行為、即ち、治療による人体への処理行為を含まない概念である。 The use of the present invention includes, for example, anti-obesity, prevention or treatment of obesity-related diseases, hypermetabolism, improvement of eating disorders, or use of the cyclic dipeptide or a salt thereof for suppressing appetite, It is not limited to these. Further, the use is a use in a human or non-human animal, and may be a therapeutic use or a non-therapeutic use. Here, "non-therapeutic" is a concept that does not include medical treatment, that is, treatment of a human body by treatment.
７．メラニン凝集ホルモンのその受容体への結合を阻害する方法
本発明の一態様は、アミノ酸を構成単位とする特定の環状ジペプチド又はその塩を有効成分として使用する、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法である。当該方法は、好ましくは、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として使用することを含む、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として使用することを含む、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法である。 7. Method for inhibiting binding of melanin-concentrating hormone to its receptor One embodiment of the present invention is directed to a melanin-concentrating hormone receptor for melanin-concentrating hormone using a specific cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient. Is a method of inhibiting the binding to. The method is preferably cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl leucine. [Cyclo (Ala-Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloroyl Sylphenylalanine [Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloglutaminylleucine [Cyclo (Gln-Leu)], cyclo Alanylphenylalanine (Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)], Cyclo (Gly-Lys) And melanin-concentrating hormone of melanin-concentrating hormone, which comprises using one or more cyclic dipeptides selected from the group consisting of cycloalanilvaline [Cyclo (Ala-Val)] or a salt thereof as an active ingredient. It is a method of inhibiting binding to a receptor. More preferably, it is a method of inhibiting the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor, which comprises using, as an active ingredient, one containing three or more selected from the above cyclic dipeptides or salts thereof.
当該方法に関する別の態様は、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合阻害を必要とする対象に、特定の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法である。好ましくは、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上の環状ジペプチド又はその塩を有効成分として治療有効量を投与することを含む、メラニン凝集ホルモンのメラニン凝集ホルモン受容体への結合を阻害する方法である。より好ましくは、前記環状ジペプチド又はその塩から選択される３つ以上を含むものを有効成分として治療有効量を投与することを含む、メラニン凝集ホルモンのその受容体への結合を阻害する方法である。 Another embodiment of the method comprises administering a therapeutically effective amount of a specific cyclic dipeptide or a salt thereof as an active ingredient to a subject in need of inhibiting the binding of melanin-concentrating hormone to the melanin-concentrating hormone receptor. This is a method of inhibiting the binding of the agglutinating hormone to the melanin aggregating hormone receptor. Preferably, cycloarginyl leucine (Cyclo (Arg-Leu)), cycloglutaminyl arginine (Cyclo (Gln-Arg)), cycloleucyl lysine (Cyclo (Leu-Lys)), cycloalanyl leucine (Cyclo (Ala -Leu)], cycloaspartyl serine [Cyclo (Asp-Ser)], cyclolysyl tyrosine [Cyclo (Lys-Tyr)], cycloarginyl aspartic acid [Cyclo (Arg-Asp)], cycloleucyl phenylalanine [Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysylphenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], cycloalanylphenylalanine [ Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)], cycloglycyllysine [Cyclo (Gly-Lys)], and shiku Melanin-concentrating hormone receptor for melanin-concentrating hormone, comprising administering a therapeutically effective amount of one or more cyclic dipeptides selected from the group consisting of alanylvaline [Cyclo (Ala-Val)] or a salt thereof as an active ingredient It is a method of inhibiting binding to the body. More preferred is a method of inhibiting the binding of melanin-concentrating hormone to its receptor, which comprises administering a therapeutically effective amount of an active ingredient containing three or more selected from the above cyclic dipeptides or salts thereof. .
上記方法において、メラニン凝集ホルモンのその受容体への結合阻害を必要とする対象とは、本発明のメラニン凝集ホルモン受容体拮抗用組成物の前記適用対象と同様である。また、本明細書中において治療有効量とは、本発明のメラニン凝集ホルモン受容体拮抗用組成物を上記対象に投与した場合に、投与していない対象と比較して、メラニン凝集ホルモンのその受容体への結合が阻害される量のことである。具体的な有効量としては、投与形態、投与方法、使用目的及び対象の年齢、体重、症状等によって適宜設定され一定ではない。 In the above method, the subject requiring inhibition of binding of melanin-concentrating hormone to its receptor is the same as the subject to which the melanin-concentrating hormone receptor antagonizing composition of the present invention is applied. Further, in the present specification, a therapeutically effective amount means that when the composition for melanin-concentrating hormone receptor antagonism of the present invention is administered to the above-mentioned subject, the receptor for the melanin-concentrating hormone is compared with a subject not administered. The amount of binding to the body is inhibited. The specific effective amount is appropriately set depending on the administration form, administration method, purpose of use, age, weight, symptom of the subject, etc., and is not constant.
本発明の方法においては、前記治療有効量となるよう、前記特定の環状ジペプチド又はその塩をそのまま、或いは、特定の環状ジペプチド又はその塩を含有する組成物として投与してもよい。 In the method of the present invention, the specific cyclic dipeptide or a salt thereof may be administered as it is or as a composition containing the specific cyclic dipeptide or a salt thereof so that the therapeutically effective amount is obtained.
本発明の方法によれば、副作用を生じることなくメラニン凝集ホルモンのその受容体への結合を阻害することが可能になる。 The method of the present invention makes it possible to inhibit the binding of melanin-concentrating hormone to its receptor without causing side effects.
以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。当業者は、本発明の方法を種々変更、修飾して使用することが可能であり、これらも本発明の範囲に含まれる。 Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited thereby. Those skilled in the art can use the method of the present invention with various changes and modifications, and these are also included in the scope of the present invention.
実施例１．環状ジペプチドによるメラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）拮抗作用の検討
環状ジペプチド標品のメラニン凝集ホルモン受容体における拮抗作用を調べるため、メラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）に対する結合アッセイを実施した。具体的には、ヒトＭＣＨ１Ｒを発現させたＣＨＯ細胞（チャイニーズハムスター卵巣由来細胞）を用い、これに３０μＭのヒトＭＣＨと各種濃度の化学合成された環状ジペプチド標品とを添加して、細胞内カルシウムイオン濃度の変化を測定した。細胞内カルシウムイオン濃度は、蛍光光度分析により定量した。 Example 1. Examination of melanin-concentrating hormone receptor (MCH1R) antagonism by cyclic dipeptide In order to examine the antagonism of the cyclic dipeptide preparation at melanin-concentrating hormone receptor, a binding assay for melanin-concentrating hormone receptor (MCH1R) was carried out. Specifically, human MCH1R-expressing CHO cells (Chinese hamster ovary-derived cells) were used, to which 30 μM human MCH and various concentrations of chemically synthesized cyclic dipeptide preparations were added to give intracellular calcium. The change in ion concentration was measured. The intracellular calcium ion concentration was quantified by fluorescence spectrophotometry.
被験環状ジペプチドの拮抗作用については、環状ジペプチドを添加せず、ヒトＭＣＨのみを添加した場合の応答率（細胞内カルシウムイオン濃度の変化）を１００％とし、環状ジペプチドとヒトＭＣＨとを添加したときの応答率をその相対値（％）として算出し、その差（１００％からの減少分）を阻害率（％）として表し、評価した。その結果を表１に示す。 Regarding the antagonism of the test cyclic dipeptide, when the cyclic dipeptide was not added and only the human MCH was added, the response rate (change in intracellular calcium ion concentration) was set to 100%, and the cyclic dipeptide and human MCH were added. Was calculated as the relative value (%), and the difference (decrease from 100%) was expressed as the inhibition rate (%) for evaluation. The results are shown in Table 1.
上記の結果から、表１に示した環状ジペプチドはいずれもメラニン凝集ホルモン受容体拮抗作用を有することが明らかとなった。 From the above results, it was revealed that each of the cyclic dipeptides shown in Table 1 has a melanin-concentrating hormone receptor antagonistic action.
実施例２．茶ペプチド熱処理物と大豆ペプチド熱処理物によるメラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）拮抗作用の検討
（１）茶ペプチド熱処理物の調製
植物体として、鹿児島県産の一番茶茶葉（品種：やぶきた、全窒素：６．３％）を用いた。この茶に対して、まず、水溶性タンパク質を低減する前処理（３回の前抽出）を行った。すなわち、茶１０ｇに対して、熱湯２００ｇを加えて適宜攪拌し、５分間抽出を行った。抽出終了後、１４０メッシュでろ過し、抽出残渣（茶滓）を回収した。この茶滓に対して、２００ｇの熱湯を注ぎ５分間抽出を行って茶滓を回収した。再度、この茶滓に対して同様に抽出処理を行い茶滓を回収した。 Example 2. Examination of melanin-concentrating hormone receptor (MCH1R) antagonism by heat-treated tea peptide and heat-treated soybean peptide (1) Preparation of heat-treated tea peptide As a plant, Ichibancha tea leaves (cultivar: Yabukita, total nitrogen) produced in Kagoshima prefecture : 6.3%) was used. This tea was first subjected to pretreatment (three times of pre-extraction) to reduce water-soluble proteins. That is, 200 g of boiling water was added to 10 g of tea, and the mixture was appropriately stirred and extracted for 5 minutes. After the extraction was completed, the mixture was filtered through 140 mesh to collect the extraction residue (tea dregs). 200 g of boiling water was poured into this tea residue and extraction was performed for 5 minutes to recover the tea residue. Again, this tea residue was subjected to the same extraction treatment in the same manner to recover the tea residue.
次に、この前抽出を行った茶（茶滓）に対して、酵素による分解処理を行った。茶滓（全量）に対して５０℃の湯を２００ｇ注ぎ、プロテアーゼ（商品名：プロチンNY100、大和化成社製）を１ｇ添加し、攪拌子で攪拌（３００ｒｐｍ）しながら、５５℃のウォーターバス内にて３時間反応させた。その後、９５℃、３０分間保持して酵素を失活させた。 Next, the pre-extracted tea (tea dregs) was subjected to a decomposition treatment with an enzyme. Pour 200g of hot water at 50 ℃ into the tea dregs (total amount), add 1g of protease (trade name: Protin NY100, manufactured by Daiwa Kasei Co., Ltd.), and stir with a stir bar (300rpm) in a water bath at 55 ℃. Was reacted for 3 hours. Then, the enzyme was inactivated by holding at 95 ° C for 30 minutes.
この酵素処理液を固液分離せずに茶液体混合物の形態で、加熱処理を施した。加熱処理は、オートクレーブ（トミー精工社製）に入れて、１３５℃、３時間の高温高圧流体による加熱処理とした。処理後の液体を１４０メッシュでろ過し、茶ペプチド熱処理物を得た。
（２）大豆ペプチド熱処理物の調製
大豆ペプチド熱処理物として、大豆ペプチドを加熱処理したものを用いた。大豆ペプチド熱処理物は、大豆ペプチドを液体中にて高温高圧処理して製造した。具体的には、大豆ペプチド（ハイニュートAM、不二製油社製）３ｇに、それぞれ約１５ｍｌの蒸留水を加え、オートクレーブ（トミー精工社製）に入れて、１３５℃、０．３１ＭＰａ、３時間高温高圧処理を加えた。
（３）メラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）拮抗作用の評価
茶ペプチド熱処理物および大豆ペプチド熱処理物のメラニン凝集ホルモン受容体における拮抗作用を調べるため、メラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）に対する結合アッセイを実施した。具体的には、ヒトＭＣＨ１Ｒを発現させたＣＨＯ細胞（チャイニーズハムスター卵巣由来細胞）を用い、これにヒトＭＣＨ（３０μＭ）と茶ペプチド熱処理物または大豆ペプチド熱処理物（最終濃度が０．１ｍｇ／ｍｌ又は１ｍｇ／ｍｌ）とを添加して、細胞内カルシウムイオン濃度の変化を測定した。細胞内カルシウムイオン濃度は、蛍光光度分析により定量した。茶ペプチド熱処理物および大豆ペプチド熱処理物は、上記（１）及び（２）にそれぞれ記載の熱処理物をスプレードライ処理して粉末状にしたものを使用した。The enzyme treatment liquid was subjected to heat treatment in the form of a tea liquid mixture without solid-liquid separation. The heat treatment was carried out by placing in an autoclave (manufactured by Tommy Seiko Co., Ltd.) and using a high temperature and high pressure fluid at 135 ° C. for 3 hours. The treated liquid was filtered through 140 mesh to obtain a heat-treated brown peptide.
(2) Preparation of heat-treated soybean peptide As the heat-treated soybean peptide, heat-treated soybean peptide was used. The heat-treated soybean peptide was produced by treating soybean peptide in a liquid at high temperature and high pressure. Specifically, about 15 ml of distilled water was added to 3 g of soybean peptide (High New AM, manufactured by Fuji Oil Co., Ltd.), and the mixture was placed in an autoclave (manufactured by Tommy Seiko Co., Ltd.) at 135 ° C., 0.31 MPa for 3 hours. A high temperature, high pressure treatment was applied.
(3) Evaluation of melanin-concentrating hormone receptor (MCH1R) antagonism In order to investigate antagonism of melanin-concentrating hormone receptor (MCH1R) of heat-treated tea peptide and soybean peptide, a binding assay for melanin-concentrating hormone receptor (MCH1R) was conducted. did. Specifically, human MCH1R-expressing CHO cells (Chinese hamster ovary-derived cells) were used, and human MCH (30 μM) and heat-treated tea peptide or soybean peptide (final concentration 0.1 mg / ml or 1 mg / ml) was added and the change in intracellular calcium ion concentration was measured. The intracellular calcium ion concentration was quantified by fluorescence spectrophotometry. As the heat-treated tea peptide and soybean peptide, the heat-treated products described in (1) and (2) above were spray-dried into powder form.
茶ペプチド熱処理物および大豆ペプチド熱処理物の拮抗作用については、茶ペプチド熱処理物および大豆ペプチド熱処理物を添加せず、ヒトＭＣＨのみを添加した場合の応答率（細胞内カルシウムイオン濃度の変化）を１００％とし、茶ペプチド熱処理物または大豆ペプチド熱処理物とヒトＭＣＨとを添加したときの応答率をその相対値（％）として算出し、その差（１００％からの減少分）を阻害率（％）として表し、評価した。その結果を表２に示す。 Regarding the antagonistic action of the heat-treated tea peptide and the heat-treated soybean peptide, the response rate (change in intracellular calcium ion concentration) when only human MCH was added without adding the heat-treated tea peptide and soybean peptide was 100. %, The response rate of the heat-treated tea peptide or soybean peptide and human MCH was calculated as the relative value (%), and the difference (decrease from 100%) was the inhibition rate (%). It was expressed and evaluated as. The results are shown in Table 2.
上記の結果から、茶ペプチド熱処理物および大豆ペプチド熱処理物はいずれもメラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）拮抗作用を有することが明らかとなった。これらの試験素材のメラニン凝集ホルモン受容体（ＭＣＨ１Ｒ）拮抗効果には、各種素材に含まれる環状ジペプチド（例えば、表１に示された環状ジペプチド）が因子の一つとして寄与している可能性があると考えられた。 From the above results, it was revealed that both the heat-treated tea peptide and the heat-treated soybean peptide have melanin-concentrating hormone receptor (MCH1R) antagonistic activity. It is possible that the cyclic dipeptides contained in various materials (for example, the cyclic dipeptides shown in Table 1) contribute to the melanin-concentrating hormone receptor (MCH1R) antagonistic effect of these test materials as one of the factors. Thought to be.
本発明は、特定の環状ジペプチド又はその塩を有効成分として含有するメラニン凝集ホルモン受容体拮抗用組成物を提供するものである。本発明は、抗肥満等に資する新たな手段を提供するものであるため、産業上の利用性が高い。 The present invention provides a melanin-concentrating hormone receptor antagonistic composition containing a specific cyclic dipeptide or a salt thereof as an active ingredient. INDUSTRIAL APPLICABILITY The present invention provides a new means that contributes to antiobesity and the like, and thus has high industrial utility.
Claims (6)
前記環状ジペプチド又はその塩が、シクロアルギニルロイシン〔Cyclo(Arg-Leu)〕、シクログルタミニルアルギニン〔Cyclo(Gln-Arg)〕、シクロロイシルリシン〔Cyclo(Leu-Lys)〕、シクロアラニルロイシン〔Cyclo(Ala-Leu)〕、シクロアスパルチルセリン〔Cyclo(Asp-Ser)〕、シクロリシルチロシン〔Cyclo(Lys-Tyr)〕、シクロアルギニルアスパラギン酸〔Cyclo(Arg-Asp)〕、シクロロイシルフェニルアラニン〔Cyclo(Leu-Phe)〕、シクログルタミニルセリン〔Cyclo(Gln-Ser)〕、シクロリシルフェニルアラニン〔Cyclo(Lys-Phe)〕、シクログルタミニルロイシン〔Cyclo(Gln-Leu)〕、シクロアラニルフェニルアラニン〔Cyclo(Ala-Phe)〕、シクロアルギニルフェニルアラニン〔Cyclo(Arg-Phe)〕、シクロアルギニルチロシン〔Cyclo(Arg-Tyr)〕、シクロリシルセリン〔Cyclo(Lys-Ser)〕、シクログリシルリシン〔Cyclo(Gly-Lys)〕、及びシクロアラニルバリン〔Cyclo(Ala-Val)〕からなる群から選択される１つ又は２つ以上を含むものである、前記メラニン凝集ホルモン受容体拮抗用組成物。 A composition for melanin-concentrating hormone receptor antagonism containing a cyclic dipeptide having an amino acid as a constituent unit or a salt thereof as an active ingredient,
The cyclic dipeptide or a salt thereof, cycloarginyl leucine [Cyclo (Arg-Leu)], cycloglutaminyl arginine [Cyclo (Gln-Arg)], cycloleucyl lysine [Cyclo (Leu-Lys)], cycloalanyl Leucine (Cyclo (Ala-Leu)], cycloaspartyl serine (Cyclo (Asp-Ser)), cyclolysyl tyrosine (Cyclo (Lys-Tyr)), cycloarginyl aspartic acid (Cyclo (Arg-Asp)), cyclo Leucyl phenylalanine (Cyclo (Leu-Phe)], cycloglutaminyl serine [Cyclo (Gln-Ser)], cyclolysyl phenylalanine [Cyclo (Lys-Phe)], cycloglutaminyl leucine [Cyclo (Gln-Leu)], Cycloalanylphenylalanine [Cyclo (Ala-Phe)], cycloarginylphenylalanine [Cyclo (Arg-Phe)], cycloarginyltyrosine [Cyclo (Arg-Tyr)], cyclolysylserine [Cyclo (Lys-Ser)] , Cycloglycyrrhizin [Cycl o (Gly-Lys)] and cycloalanylvaline [Cyclo (Ala-Val)], and the composition for antagonizing melanin-concentrating hormone receptor, which comprises one or more selected from the group consisting of:
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