JP6291158B2 - 抗認知症および学習記憶改善剤 - Google Patents
抗認知症および学習記憶改善剤 Download PDFInfo
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- JP6291158B2 JP6291158B2 JP2012255047A JP2012255047A JP6291158B2 JP 6291158 B2 JP6291158 B2 JP 6291158B2 JP 2012255047 A JP2012255047 A JP 2012255047A JP 2012255047 A JP2012255047 A JP 2012255047A JP 6291158 B2 JP6291158 B2 JP 6291158B2
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- 230000009967 tasteless effect Effects 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Description
しかも、人工的に合成された食経験のない化合物を長期に渡って飲み続けることは、人体に対する重大な副作用の発現が懸念される。
[1] 2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する抗認知症剤。
[2] アルツハイマー型認知症の症状を改善または症状の進行を遅らせる、[1]記載の抗認知症剤。
[3] さらに抗うつ作用を有する、[1]または[2]記載の抗認知症剤。
[4] 抑うつ症状の改善または症状の進行を遅らせる、[3]の抗認知症剤。[5] さらに学習意欲の改善作用を有する、[1]記載の抗認知症剤。
[6] 経口剤である、[1]〜[5]のいずれかに記載の抗認知症剤。
[7] 2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する学習記憶改善剤。
[8] アルツハイマー型認知症の症状を改善または症状の進行を遅らせる、[7]記載の学習記憶改善剤。
[9] 経口剤である、[7]又は[8]記載の学習記憶改善剤。
<抗認知症剤および学習記憶促進剤>
本発明は、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する抗認知症剤、および2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する学習記憶改善剤である。
(1)獣畜肉類、魚介類、または、貝類を原料とし、液体中にて加熱することにより、それらに含有される水溶性タンパク質を除去する前処理工程;
(2)該前処理後に液体を交換し、再度加熱する工程;および
(3)得られた液サンプルをろ過する工程。
本発明の抗認知症剤および学習記憶改善剤には、適宜、好ましい担体、賦形剤、安定化剤、酸化防止剤、防腐剤、界面活性剤等の添加物を加えてもよい。正確な投与量は、疾患およびその重症度、年齢、性別、体重等により異なるので適宜選択すればよいが、ヒトの場合、例えば、有効成分を1回あたり0.002〜20mg/kg、また、1日数回投与する。好ましくは1日1から3回投与するが、投与の時期は特に限定されない。
SERT阻害活性は、既報(Eur J Pharmacol, 368, 277-283, 1999)に従って、3Hラベルしたイミプラミン(imipramine)がCHO細胞に発現させたヒトSERTへの結合を阻害するかを測定した。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)は、ヒトSERTへの結合を阻害することがわかった。2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)のヒトSERTへの結合を50%阻害する濃度(IC50)は、8.1μMであった。
9-11週齢の雄性SD系ラットを使用した。ラット前頭前野におけるセロトニン濃度は、既報 ( Kehr J., and Yoshitake T. (2006) Monitoring brain chemical signals by microdialysis. In: Encyclopedia of Sensors, Vol. 6. (Eds. C.A. Grimes, E.C. Dickey and M.V. Pishko) American Scientific Publishers, USA. 287-312.)の方法で、マイクロダイアリシス法で測定した。すなわち、イソフルラン麻酔下で透析プローブをラット前頭前野に埋め込んだ。埋め込み手術の5日後、無麻酔自由行動下で人工的脳脊髄液(148 mM NaCl, 4 mM KCl, 0.8 mM MgCl2, 1.4 mM CaCl2, 1.2 mM Na2HPO4, 0.3 mM NaH2PO4, pH7.2))を1μl/minの流速で灌流した。2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)は、0.5%カルボキシメチルセルロースナトリウム(CMC-Na)に懸濁して、2、20および200 mg/kgを14日間連続経口投与した。最終経口投与直前および経口投与後30分毎に採取した灌流液15μl中のアセチルコリン量をHPLC−ECD法により定量した。被検サンプルの経口投与直前を0分とし、経口投与1時間前から経口投与3時間後までの結果を図1に示す。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を20および200 mg/kg経口投与することにより、有意に前頭前野のセロトニン濃度が上昇した。
抗うつ作用は、既報(Exp Anim, 59(2), 191-197, 2010)に従って測定した。すなわち、直径90 cm、高さ35 cmの円筒状のタンクに水温22±1℃の水を水深20 cmになるように入れ、タンク内に直径10 cmの逃避台を設置した。タンクの水に酸化チタニウムを入れて白濁させ、逃避台の位置を隠した。先ず、10-11週齢の雄性C57BL/6マウスを用いてモリス水迷路試験を8日間実施し、60秒以内に逃避台に到達できないマウスを選択した(Loserマウス、上記文献では、inferiorと記載)。次に、0.5%CMC-Naに懸濁した2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)0.02、0.2、2および20 mg/kgをモリス水迷路試験の施行前に経口投与した。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)の経口投与により、用量依存的に逃避台潜時が短縮し、0.2 mg/kg以上の経口投与で有意に短縮した(図2)。以上の結果から、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)は抗うつ作用および学習意欲改善作用を有する
ことが明らかになった。
AChE阻害作用は、AChEに高い選択性を持つ基質であるMATP+(1,1-ジメチル-4-アセチルチオメチルピペリジン) (Biol Pharma Bull, 33(4), 702-706, 2010)で測定した。すなわち、AChEにMATP+を反応させ、検出試薬であるDNTB(5,5’−ジチオビス(2−ニトロ安息香酸))の反応に伴う412nmの吸光度変化を指標に測定した。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)はAChEを阻害し、50%阻害する濃度(IC50)は、3.4μMであった。
透析プローブをラット海馬に埋め込み、実施例1と同様の方法で測定した。2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)は、0.5%CMC-Naに懸濁して、200 mg/kgを単回経口投与した。経口投与直前および経口投与後30分毎に採取した灌流液15μl中のアセチルコリン量をHPLC−ECD法により定量した。被検サンプルの経口投与直前を0分とし、経口投与1時間前から経口投与3時間後までの結果を図3に示す。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)200 mg/kgの経口投与は、海馬アセチルコリン濃度を2.5倍に上昇させた。
6週齢のSD系雄性ラットを使用し、ラットは食餌制限下で習得訓練を行った後に本試験を実施した。
習得訓練
8方向放射状迷路の全てのアームの先端に餌を置き、迷路中央のプラットホームに動物を入れ、各アームの餌を全て採るまで、または動物を入れ10分が経過するまでを1試行として、1日1回の訓練を行った。正選択は、その試行において未選択のアームに入ること、誤選択は既に餌を採ったアームに入ることと定義し、最初の8選択中7選択以上の試行を基準試行とし、この成績が3試行連続するまで訓練を行った。
本試験
上記習得訓練試行において基準を達成したラットに2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を0.5%CMC-Naに懸濁して、20 および200mg/kg経口投与した。経口投与10分後にスコポラミン0.5 mg/kgを腹腔内投与した。スコポラミンの腹腔内投与30分後に8方向放射状迷路試験を実施し、誤選択数と全ての餌を採り終えるまでに要した時間を計測した。また、陽性対照として、被験サンプルの代わりに塩酸ドネペジル(アリセプト)を2 mg/kg経口投与した。5分間、または、8ヵ所全ての餌を食べるまでの総試行中の正選択率の結果を図4に示す。その結果、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)の経口投与は、正答率を有意に改善した。以上の結果から、2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)に学習記憶改善作用があることが明らかになった。
Claims (7)
- 2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する抗認知症剤であって、アルツハイマー型認知症の症状を改善または症状の進行を遅らせるための、前記抗認知症剤。
- さらに抗うつ作用を有する、請求項1記載の抗認知症剤。
- 抑うつ症状の改善または症状の進行を遅らせる、請求項2記載の抗認知症剤。
- さらに学習意欲の改善作用を有する、請求項1記載の抗認知症剤。
- 経口剤である、請求項1〜4のいずれかに記載の抗認知症剤。
- 2,5-ピペラジンジオン,3,6-ビス(フェニルメチル)-,(3S,6S)を有効成分として含有する学習記憶改善剤であって、アルツハイマー型認知症の症状を改善または症状の進行を遅らせるための、前記学習記憶改善剤。
- 経口剤である、請求項6記載の学習記憶改善剤。
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PH12015501115A1 (en) | 2015-08-10 |
NZ708648A (en) | 2019-08-30 |
CN104936597B (zh) | 2019-01-11 |
AU2013348836B2 (en) | 2018-08-16 |
US20150297584A1 (en) | 2015-10-22 |
KR20150086357A (ko) | 2015-07-27 |
SG11201503967QA (en) | 2015-06-29 |
KR102142168B1 (ko) | 2020-08-06 |
JP2014101324A (ja) | 2014-06-05 |
GB2523044A (en) | 2015-08-12 |
WO2014080973A1 (ja) | 2014-05-30 |
SG10201909517WA (en) | 2019-11-28 |
MY183914A (en) | 2021-03-17 |
US9877960B2 (en) | 2018-01-30 |
TW201436794A (zh) | 2014-10-01 |
AU2013348836A1 (en) | 2015-07-02 |
GB2523044B (en) | 2019-03-27 |
HK1211212A1 (en) | 2016-05-20 |
GB201509976D0 (en) | 2015-07-22 |
TWI620564B (zh) | 2018-04-11 |
PH12015501115B1 (en) | 2015-08-10 |
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