JPH06279311A - Activation agent for protein kinase c isozyme - Google Patents
Activation agent for protein kinase c isozymeInfo
- Publication number
- JPH06279311A JPH06279311A JP5090522A JP9052293A JPH06279311A JP H06279311 A JPH06279311 A JP H06279311A JP 5090522 A JP5090522 A JP 5090522A JP 9052293 A JP9052293 A JP 9052293A JP H06279311 A JPH06279311 A JP H06279311A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- phosphatidylserine
- protein kinase
- formula
- acyl residue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規な老人性痴呆症治
療薬として期待される、特定の脂肪酸よりなるホスファ
チジルセリン誘導体を有効成分とするプロテインキナー
ゼＣアイソザイムβまたはγの活性化剤に関する。TECHNICAL FIELD The present invention relates to a protein kinase C isozyme β or γ activator containing a phosphatidylserine derivative consisting of a specific fatty acid as an active ingredient, which is expected as a novel therapeutic drug for senile dementia.
【０００２】[0002]
【従来の技術】近年、平均寿命の延長と共に、高齢者が
急激に増加し、高齢化社会としての様々な問題が生じて
いる。なかでも、老人性痴呆症の増加は大きな問題であ
る。老人性痴呆症は大別して、脳血管性痴呆とアルツハ
イマー型痴呆（ＳＤＡＴ）とに分けられる。アルツハイ
マー型痴呆は従来は、欧米諸国に比べて我が国での頻度
は低いとされていた。しかしながら、近年の成人病の疾
病構造の変化と共に、今後我が国でも急激な増加が予想
されており、その発症、進展の機構について精力的な研
究が進められている。ＳＤＡＴにおける１つの仮説は、
アセチルコリン作動系が異常をきたし、コリンアセチル
転移酵素活性が低下して脳内アセチルコリンが減少し、
記憶や知能に影響を及ぼしているというものである（中
村重信、医学のあゆみ，145, p. 291 (1988)）。このよ
うに、神経機能の障害が関与していると考えられること
から、脳内に高濃度に存在するプロテインキナーゼＣ
（脳内の種々のリン酸化酵素）がＳＤＡＴ発症に関係す
るものとして注目されている。2. Description of the Related Art In recent years, as the average life span has been extended, the number of elderly people has increased rapidly, and various problems have arisen as an aging society. Among them, the increase of senile dementia is a big problem. Senile dementia is roughly divided into cerebrovascular dementia and Alzheimer's dementia (SDAT). Traditionally, Alzheimer's dementia was considered to be less frequent in Japan than in Western countries. However, along with recent changes in the disease structure of adult diseases, a sharp increase is expected in Japan in the future as well, and vigorous research is being conducted on the mechanism of its onset and progress. One hypothesis in SDAT is
The acetylcholinergic system becomes abnormal, choline acetyltransferase activity decreases, and acetylcholine in the brain decreases,
It affects memory and intelligence (Shigenobu Nakamura, Ayumi of Medicine, 145, p. 291 (1988)). Thus, since it is considered that the impairment of nerve function is involved, protein kinase C present in high concentration in the brain
(Various phosphorylating enzymes in the brain) have attracted attention as being related to the development of SDAT.
【０００３】プロテインキナーゼＣにはアイソザイム
α、β、γが存在することが知られている。このうち、
α型はほとんどすべての組織に存在している。β型は、
脳、肝臓等の組織に局在し、アルツハイマー病患者の脳
（側頭葉組織膜画分）で減少し、かつ海馬膜分画におい
て免疫反応性が低下していることが報告されている（下
濱 俊ら、第３５回日本神経化学会大会論文集，p. 92
(1992)； Maslish E., Cole G., Shimohama S., Hansen
L., De Teresa R., Terry R. D., and Saitoh T., 10,
pp. 2113-2124 (1990)；下濱 俊、最近医学，47, p. 6
02 (1992)）。γ型については、中枢神経系のみに存在
し、とくに海馬、大脳、小脳の皮質にも局在し、シナプ
スの長期増強、いわゆる記憶の現象に関与したり、神経
刺激伝達やチャンネルの修飾などシナプスの可塑性に関
係していることが知られている（西塚泰美、化学と工
業，44, p. 123 (1991)）。It is known that protein kinase C has isozymes α, β and γ. this house,
Alpha type is present in almost all tissues. β type is
It has been reported that it is localized in tissues such as brain and liver, decreases in the brain (temporal lobe tissue membrane fraction) of Alzheimer's disease patients, and immunoreactivity is reduced in the hippocampal membrane fraction ( Shun Shimohama et al., Proc. Of the 35th Annual Meeting of the Japanese Society for Neurochemistry, p. 92
(1992); Maslish E., Cole G., Shimohama S., Hansen
L., De Teresa R., Terry RD, and Saitoh T., 10,
pp. 2113-2124 (1990); Shun Shimohama, Recent Medicine, 47, p. 6
02 (1992)). About γ type, it exists only in the central nervous system, and is also localized in the hippocampus, cerebrum, and cerebellar cortex, and is involved in long-term synaptic enhancement, so-called memory phenomenon, and in synaptic transmission such as nerve stimulation transmission and channel modification. It is known that it is related to the plasticity of (Yasutsumi Nishitsuka, Kagaku to Kogyo, 44, p. 123 (1991)).
【０００４】これらプロテインキナーゼＣは西塚らによ
って発見されたカルシウム依存性の蛋白リン酸化酵素の
一種で、種々の細胞内情報伝達系において中心的な役割
を果たすことが、近年報告されている。It has been recently reported that these protein kinases C are one of the calcium-dependent protein kinases discovered by Nishitsuka et al. And play a central role in various intracellular signal transduction systems.
【０００５】例えば、Pepeuらの研究では、老齢脳のア
セチルコリンの放出は、若齢のものに比べ４０％低下し
ていたが、牛脳のホスファチジルセリンを８日間投与し
たところ、６割程度の回復が認められている（F. Casam
enti, C. Scali, and G. Pepeu, Eur. J. Pharmacol.,
194, p. 11 (1991)）。また、臨床的には、Amaducciら
とSMIDグループは、アルツハイマー型痴呆症の疑いのあ
る１４２名の患者を対象に牛脳ホスファチジルセリンと
プラセボを投与した結果、３ヵ月の治療後、重症度の高
い群では２０の心理的尺度のうち３つでプラセボ群より
も実薬群の成績が優れていたと報告されている（L. Ama
ducci et al., Psychopharmacology Bulletin, 24, p.
130 (1988)）。For example, in the study by Pepeu et al., The release of acetylcholine in the aged brain was 40% lower than that in the aged brain, but when phosphatidylserine in bovine brain was administered for 8 days, the recovery was about 60%. Is recognized (F. Casam
enti, C. Scali, and G. Pepeu, Eur. J. Pharmacol.,
194, p. 11 (1991)). Clinically, Amaducci et al. And the SMID group administered bovine brain phosphatidylserine and placebo to 142 patients suspected of having Alzheimer's dementia, which resulted in high severity after 3 months of treatment. In the group, three out of twenty psychological measures were reported to outperform the active group over the placebo group (L. Ama
ducci et al., Psychopharmacology Bulletin, 24, p.
130 (1988)).
【０００６】しかしながら、天然物である牛脳ホスファ
チジルセリンを医薬として用いることは、生体からの蛋
白質の混入等を考えると問題が多い。また、牛脳ホスフ
ァチジルセリンは、種々の脂肪酸から構成される混合物
であり、構成脂肪酸組成を特定した場合に、どのような
活性が発現するかは全く調べられていない。However, using bovine brain phosphatidylserine, which is a natural product, as a medicine has many problems in consideration of contamination of proteins from the living body. Further, bovine brain phosphatidylserine is a mixture composed of various fatty acids, and what kind of activity is expressed when the constituent fatty acid composition is specified has not been investigated at all.
【０００７】[0007]
【発明が解決しようとする課題】本発明は、蛋白質等の
不純物の混入の心配がなく、プロテインキナーゼＣ、と
くにそのアイソザイムβ及びγ活性化能の高いプロテイ
ンキナーゼＣ活性化剤を提供することを目的とする。DISCLOSURE OF THE INVENTION The present invention provides a protein kinase C activator having a high ability to activate protein kinase C, particularly isozyme β and γ thereof, without concern about contamination of impurities such as proteins. To aim.
【０００８】[0008]
【課題を解決するための手段】本発明者等は、分子種の
明確なホスファチジルセリンを合成し、これらについて
プロテインキナーゼＣアイソザイムの活性化について種
々検討したところ、特定の脂肪酸を構成成分とするホス
ファチジルセリンのみがアイソザイムβ及びγに対する
強い活性化能を有することを見いだし、本発明を完成す
るに至った。The inventors of the present invention synthesized phosphatidylserine having a well-defined molecular species, and studied various activations of protein kinase C isozymes for these phosphatidylserines. As a result, phosphatidyl containing a specific fatty acid as a constituent component. It was found that only serine has a strong ability to activate isozymes β and γ, and the present invention has been completed.
【０００９】すなわち本発明は、一般式［Ｉ］That is, the present invention has the general formula [I]
【００１０】[0010]
【化３】 [Chemical 3]
【００１１】（式中、Ｒ1はミリスチン酸、パルミチン
酸、またはステアリン酸のアシル残基を表わし、Ｒ2は
リノール酸、リノレン酸、アラキドン酸、またはドコサ
ヘキサエン酸のアシル残基を表わす）で表わされるホス
ファチジルセリン誘導体又はその薬学上許容しうる塩を
有効成分とするプロテインキナーゼＣアイソザイムα又
はγの活性化剤に関する。(Wherein R 1 represents an acyl residue of myristic acid, palmitic acid, or stearic acid, and R 2 represents an acyl residue of linoleic acid, linolenic acid, arachidonic acid, or docosahexaenoic acid). The present invention relates to an activator of protein kinase C isozyme α or γ containing a phosphatidylserine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【００１２】薬学上許容しうる塩としては、ナトリウム
塩、カリウム塩、マグネシウム塩、カルシウム塩、アン
モニウム塩、リン酸塩、塩酸塩、硫酸塩、酢酸塩等を例
示することができるが、とくにナトリウム塩及びカリウ
ム塩が好ましい。Examples of the pharmaceutically acceptable salt include sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, phosphate salt, hydrochloride salt, sulfate salt, acetate salt, and the like. Salts and potassium salts are preferred.
【００１３】上記一般式で表わされるホスファチジルセ
リン誘導体としては、例えば、 １-ミリストイル-２-リノレオイル-ホスファチジルセリ
ン １-ミリストイル-２-リノレノイル-ホスファチジルセリ
ン １-ミリストイル-２-アラキドノイル-ホスファチジルセ
リン １-ミリストイル-２-ドコサヘキサノイル-ホスファチジ
ルセリン １-パルミトイル-２-リノレオイル-ホスファチジルセリ
ン １-パルミトイル-２-リノレノイル-ホスファチジルセリ
ン １-パルミトイル-２-アラキドノイル-ホスファチジルセ
リン １-パルミトイル-２-ドコサヘキサノイル-ホスファチジ
ルセリン １-ステアロイル-２-リノレオイル-ホスファチジルセリ
ン １-ステアロイル-２-リノレノイル-ホスファチジルセリ
ン １-ステアロイル-２-アラキドノイル-ホスファチジルセ
リン １-ステアロイル-２-ドコサヘキサノイル-ホスファチジ
ルセリン 等を挙げることができる。Examples of the phosphatidylserine derivative represented by the above general formula include 1-myristoyl-2-linoleoyl-phosphatidylserine 1-myristoyl-2-linolenoyl-phosphatidylserine 1-myristoyl-2-arachidonoyl-phosphatidylserine 1-myristoyl. -2-docosahexanoyl-phosphatidylserine 1-palmitoyl-2-linoleoyl-phosphatidylserine 1-palmitoyl-2-linolenoyl-phosphatidylserine 1-palmitoyl-2-arachidonoyl-phosphatidylserine 1-palmitoyl-2-docosahexanoyl Serine 1-stearoyl-2-linoleoyl-phosphatidylserine 1-stearoyl-2-linolenoyl-phosphatidylserine 1-stearoyl-2-arachidonoyl-phosphatidylserine 1-su Aroyl-2-docosapentaenoic hexanoyl - can be exemplified phosphatidylserine like.
【００１４】これらの化合物は、特願昭５２−８９６２
２号公報に記載された方法により得られる混酸型１，２
−ジアシル-ホスファチジルコリンを、特願昭６１−２
３８７９３号公報に記載の方法により塩基交換すること
により製造される。These compounds are disclosed in Japanese Patent Application No. 52-8962.
Mixed acid type 1, 2 obtained by the method described in JP-A-2
-Diacyl-phosphatidylcholine was prepared according to Japanese Patent Application No. 61-2
It is produced by the base exchange according to the method described in 38793.
【００１５】すなわち、グリセロホスホリルコリンを出
発原料として、化学合成により目的の脂肪酸を有する単
酸型１，２−ジアシル-ホスファチジルコリンを得、次
いでホスホリパーゼＡ2の酵素反応により、目的の脂肪
酸を有する１−アシルグリセロホスホリルコリンを得
る。さらに、１−アシルグリセロホスホリルコリンから
所望の高度不飽和脂肪酸を化学合成により２位に導入
し、混酸型１，２−ジアシル-ホスファチジルコリンを
得、次いでホスホリパーゼＤの酵素反応により、目的の
混酸型１，２−ジアシル-ホスファチジルセリンを得る
ことができる。That is, a monoacid type 1,2-diacyl-phosphatidylcholine having a target fatty acid is obtained by chemical synthesis using glycerophosphorylcholine as a starting material, and then 1-acylglycero having the target fatty acid is obtained by enzymatic reaction of phospholipase A2. Get phosphorylcholine. Further, desired polyunsaturated fatty acid is introduced from the 1-acyl glycerophosphorylcholine to the 2-position by chemical synthesis to obtain mixed acid type 1,2-diacyl-phosphatidylcholine, and then by enzymatic reaction of phospholipase D, the desired mixed acid type 1, 2-diacyl-phosphatidylserine can be obtained.
【００１６】さらに本発明は、下記一般式［ＩＩ］Furthermore, the present invention provides the following general formula [II]
【化４】 （式中、Ｒ3およびＲ4は独立に、炭素数１２〜２２の脂
肪酸のアシル残基を表わす）で表わされるジアシルグリ
セロールをさらに含有することを特徴とする、一般式
［Ｉ］で表わされるホスファチジルセリン誘導体又はそ
の薬学上許容しうる塩を有効成分とするプロテインキナ
ーゼＣアイソザイムβ又はγの活性化剤に関する。[Chemical 4] (In the formula, R 3 and R 4 independently represent an acyl residue of a fatty acid having 12 to 22 carbon atoms), and further contains a diacylglycerol represented by the general formula [I] The present invention relates to an activator of protein kinase C isozyme β or γ containing a phosphatidylserine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
【００１７】上記一般式［ＩＩ］で表わされるジアシル
グリセロールを構成する炭素数１２〜２２の脂肪酸とし
ては、オレイン酸、エライジン酸、エルカ酸、ミリスチ
ン酸、パルミチン酸、ベヘン酸等を例示することができ
る。Examples of the fatty acid having 12 to 22 carbon atoms which constitutes the diacylglycerol represented by the above general formula [II] include oleic acid, elaidic acid, erucic acid, myristic acid, palmitic acid and behenic acid. it can.
【００１８】上記一般式［Ｉ］で表わされるホスファチ
ジルセリン誘導体は、トリトンＸ−１００を用いたミッ
クスミセル法によるプロテインキナーゼＣ活性化能の測
定から、とくに上記一般式［ＩＩ］で表わされるジアシ
ルグリセロール存在下に、強い活性化能を有することが
明らかとなった。ちなみに、上記一般式［Ｉ］で表わさ
れるホスファチジルセリン誘導体のうち、飽和脂肪酸よ
り構成されるホスファチジルセリン（以下、飽和型ホス
ファチジルセリンとも称する）や不飽和度が１である脂
肪酸残基を２位に有するものは活性が弱く、また、高度
不飽和脂肪酸であるイコサペンタエン酸残基を有するも
のも活性が低く、特定の不飽和脂肪酸を２位に有するこ
とが強い活性の発現に必須であることが認められた。The phosphatidylserine derivative represented by the general formula [I] is a diacylglycerol represented by the general formula [II] from the measurement of protein kinase C activating ability by the mixed micelle method using Triton X-100. It was revealed that it has a strong activation ability in the presence. By the way, among the phosphatidylserine derivatives represented by the above general formula [I], a phosphatidylserine composed of saturated fatty acids (hereinafter, also referred to as saturated phosphatidylserine) and a fatty acid residue having a degree of unsaturation of 1 are placed at the 2nd position. Those having a weak activity, and those having an icosapentaenoic acid residue, which is a highly unsaturated fatty acid, also have a low activity, and it is recognized that having a specific unsaturated fatty acid at the 2-position is essential for the expression of a strong activity. Was given.
【００１９】本発明の活性化剤は、治療のために経口的
あるいは非経口的に投与することができる。経口投与剤
としては散剤、顆粒剤、カプセル剤、錠剤などの固形製
剤あるいはシロップ剤、エリキシル剤などの液状製剤と
することができる。また、非経口投与剤として注射剤、
直腸投与剤、皮膚外用剤、吸入剤とすることができる。
これらの製剤は活性成分に薬学的に認容である製造助剤
を加えることにより常法に従って製造される。更に公知
の技術により持続性製剤とすることも可能である。The activator of the present invention can be administered orally or parenterally for therapeutic purposes. As the orally-administered agent, solid preparations such as powder, granules, capsules and tablets, or liquid preparations such as syrups and elixirs can be used. In addition, injections as parenteral agents,
It can be used as a rectal administration agent, external preparation for skin, and inhalation agent.
These formulations are manufactured in a conventional manner by adding to the active ingredient a pharmaceutically acceptable manufacturing auxiliary agent. Further, it is also possible to prepare a sustained-release preparation by a known technique.
【００２０】経口投与用の固形製剤を製造するには、活
性成分と、賦形剤、例えば乳糖、デンプン、結晶セルロ
ース、乳糖カルシウム、メタケイ酸アルミン酸マグネシ
ウム、無水ケイ酸などとを混合して散剤とするか、さら
に必要に応じて白糖、ヒドロキシプロピルセルロース、
ポリビニルピロリドンなどの結合剤、カルボキシメチル
セルロース、カルボキシメチルセルロースカルシウムな
どの崩壊剤などを加えて湿式又は乾式造粒して顆粒剤と
する。錠剤を製造するにはこれらの散剤及び顆粒剤をそ
のままあるいはステアリン酸マグネシウム、タルクなど
の滑沢剤加えて打錠すればよい。これらの顆粒又は錠剤
はヒドロキシプロピルメチルセルロースフタレート、メ
タアクリル酸、メタアクリル酸メチルコポリマーなどの
腸溶性基剤で被覆して腸溶性製剤、あるいはエチルセル
ロース、カルナウバロウ、硬化油などで被覆して持続性
製剤とすることもできる。また、カプセル剤を製造する
には散剤又は顆粒剤を硬カプセルに充填するか、活性成
分をグリセリン、ポリエチレングリコール、ゴマ油、オ
リーブ油などに溶解したのちゼラチン膜で被覆し軟カプ
セル剤とすることができる。In order to prepare a solid preparation for oral administration, an active ingredient is mixed with an excipient such as lactose, starch, crystalline cellulose, calcium lactose, magnesium aluminometasilicate, anhydrous silicic acid and the like to prepare a powder. Or, if necessary, sucrose, hydroxypropyl cellulose,
Wet or dry granulation is performed by adding a binder such as polyvinylpyrrolidone or the like and a disintegrating agent such as carboxymethylcellulose or carboxymethylcellulose calcium to obtain granules. In order to produce tablets, these powders and granules may be tableted as they are or by adding a lubricant such as magnesium stearate or talc. These granules or tablets are coated with an enteric base such as hydroxypropylmethylcellulose phthalate, methacrylic acid, and a methyl methacrylate copolymer to form an enteric preparation, or coated with ethylcellulose, carnauba wax, hardened oil, etc. to form a sustained-release preparation. You can also do it. In order to produce capsules, powder or granules can be filled into hard capsules, or the active ingredient can be dissolved in glycerin, polyethylene glycol, sesame oil, olive oil, etc. and then coated with a gelatin film to give soft capsules. .
【００２１】経口投与用の液状製剤を製造するには活性
成分と白糖、ソルビトール、グリセリンなどの甘味剤と
を水に溶解して透明なシロップ剤、更に精油、エタノー
ルなどを加えてエリキシル剤とするか、アラビアゴム、
トラガント、ポリソルベート８０、カルボキシメチルセ
ルロースナトリウムなどを加えて乳剤又は懸濁剤として
もよい。これらの液状製剤には所望により矯味剤、着色
剤、保存剤などを加えてもよい。In order to produce a liquid preparation for oral administration, an active ingredient and a sweetener such as sucrose, sorbitol and glycerin are dissolved in water to prepare a transparent syrup, and essential oil, ethanol and the like are added to prepare an elixir. Or gum arabic,
An emulsion or suspension may be prepared by adding tragacanth, polysorbate 80, sodium carboxymethyl cellulose and the like. If desired, flavoring agents, coloring agents, preservatives and the like may be added to these liquid preparations.
【００２２】注射剤を製造するには活性成分を必要に応
じ塩酸、水酸化ナトリウム、乳剤、乳酸ナトリウム、リ
ン酸一水素ナトリウム、リン酸二水素ナトリウムなどの
ｐＨ調整剤、塩化ナトリウム、ブドウ糖などの等張化剤
とともに注射用蒸留水に溶解し、無菌濾過してアンプル
に充填するか、更にマンニトール、デキストリン、シク
ロデキストリン、ゼラチンなどを加えて真空下凍結乾燥
し、用時溶解型の注射剤としてもよいし、活性成分にレ
シチン、ポリソルベート８０、ポリオキシエチレン硬化
ヒマシ油などを加えて水中で乳化せしめ注射用乳剤とす
ることもできる。In order to produce an injectable preparation, an active ingredient may be added, if necessary, to hydrochloric acid, sodium hydroxide, emulsion, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and other pH adjusting agents, sodium chloride, glucose, etc. It is dissolved in distilled water for injection with an isotonicity agent, aseptically filtered and filled into an ampoule, or mannitol, dextrin, cyclodextrin, gelatin, etc. are added and freeze-dried under vacuum to prepare a solution-type injection before use. Alternatively, lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. may be added to the active ingredient and emulsified in water to give an emulsion for injection.
【００２３】直腸投与剤を製造するには活性成分及びカ
カオ脂、脂肪酸のトリ、ジ及びモノグリセリド、ポリエ
チレングリコールなどの坐剤用基剤とを加湿して溶融し
型に流しこんで冷却するか、活性成分をポリエチレング
リコール、大豆油などに溶解したのちゼラチン膜で被覆
すればよい。To prepare a rectal preparation, the active ingredient and a suppository base such as cocoa butter, fatty acid tri-, di- and monoglycerides, polyethylene glycol and the like are moistened and melted and poured into a mold to cool. The active ingredient may be dissolved in polyethylene glycol, soybean oil or the like and then coated with a gelatin film.
【００２４】皮膚外用剤を製造するには活性成分を白色
ワセリン、ミツロウ、流動パラフィン、ポリエチレング
リコールなどに加えて必要ならば加湿して練合し軟膏剤
とするか、ロジン、アクリル酸アルキルエステル重合体
などの粘着剤と練合したのちポリエチレンなどの不織布
に展延してテープ剤とする。吸入剤を製造するには活性
成分をフロンガスなどの噴射剤に溶解又は分散して耐圧
容器に充填しエアゾール剤とする。To prepare an external preparation for the skin, the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to form an ointment, or rosin, an alkyl acrylate ester After kneading with an adhesive such as coalescing, it is spread on a non-woven fabric such as polyethylene to form a tape. To produce an inhalant, the active ingredient is dissolved or dispersed in a propellant such as CFC gas and filled in a pressure resistant container to form an aerosol.
【００２５】本発明の活性化剤の投与量は、ホスファチ
ジルセリンまたはその薬学上許容しうる塩の重量とし
て、患者の年齢、体重及び病態によって異なるが、通常
１日約１ｍｇ〜１０００mgであり、１乃至数回に分けて
投与することが望ましい。The dose of the activator of the present invention varies depending on the age, weight and pathological condition of the patient as the weight of phosphatidylserine or a pharmaceutically acceptable salt thereof, but is usually about 1 mg to 1000 mg per day. It is desirable to administer it in divided doses.
【００２６】[0026]
【実施例】以下、本発明を実施例及び試験例により詳細
に説明する。ただし、本発明はこれらの実施例、試験例
に限定されるものではない。EXAMPLES The present invention will be described in detail below with reference to examples and test examples. However, the present invention is not limited to these examples and test examples.
【００２７】参考例 １ （ａ）１-ステアロイル-２-リノレオイルホスファチジ
ルコリンの合成 リノール酸（９９％）２．５３ｇ（９ｍｍｏｌ）とＮ，
Ｎ’−カルボニルジイミダゾール１．７５ｇ（１０．８
ｍｍｏｌ）を無水テトラヒドロフランに溶解し、窒素気
流下室温で約１時間反応させた。ついで、この反応液に
１−ステアロイル−Ｌ−３−グリセロホスホリルコリン
１．６３ｇ（３ｍｍｏｌ）を加え、さらに触媒として、
水素化ナトリウム（４０％）４００ｍｇとイミダゾール
１ｇとを乾燥ジメチルスルホキシド（以下、ＤＭＳＯと
略す）１０ｍｌ中で約１時間反応させて調製したイミダ
ゾールナトリウム−ＤＭＳＯ溶液（２．７ｍｌ）及び無
水ピリジン１．５ｍｌを加えた後、室温にて３時間反応
させた。終了後、反応液を１Ｎ塩酸−メタノールで中和
し、クロロホルム−メタノール（２：１）３００ｍｌ、
水６０ｍｌを加えて分液ロートで分液し、下層を分取し
て減圧濃縮した。濃縮液は、クロロホルム−メタノール
−水（６５：２５：４）１００ｍｌ，エタノール１００
ｍｌ，アンバーライトＭＢ−３型樹脂４０ｍｌを加えて
処理後、樹脂をろ別し、得られたろ液を減圧濃縮した。
この濃縮物を少量のクロロホルムに溶解し、あらかじめ
クロロホルムで活性化したシリカゲル（１００ｇ）カラ
ムにかけ、クロロホルム−メタノール（９：１）６００
ｍｌ，クロロホルム−メタノール−水（６５：２５：
４）１０００ｍｌで順次溶出させた。得られた溶出分画
からＴＬＣ分析を指標として目的画分を集め、目的物
２．５７ｇ（８０％）を得た。Reference Example 1 (a) Synthesis of 1-stearoyl-2-linoleoylphosphatidylcholine 2.53 g (9 mmol) of linoleic acid (99%), N,
1.75 g (10.8 g) of N'-carbonyldiimidazole
(mmol) was dissolved in anhydrous tetrahydrofuran and reacted at room temperature under a nitrogen stream for about 1 hour. Then, 1.63 g (3 mmol) of 1-stearoyl-L-3-glycerophosphorylcholine was added to this reaction solution, and as a catalyst,
Imidazole sodium-DMSO solution (2.7 ml) prepared by reacting 400 mg of sodium hydride (40%) with 1 g of imidazole in 10 ml of dry dimethyl sulfoxide (hereinafter abbreviated as DMSO) for about 1 hour and 1.5 ml of anhydrous pyridine. After adding, the mixture was reacted at room temperature for 3 hours. After the completion, the reaction solution was neutralized with 1N hydrochloric acid-methanol, and chloroform-methanol (2: 1) 300 ml,
Water (60 ml) was added, and the mixture was separated with a separating funnel. The lower layer was separated and concentrated under reduced pressure. The concentrate was 100 ml of chloroform-methanol-water (65: 25: 4) and 100 ml of ethanol.
ml and Amberlite MB-3 type resin (40 ml) were added for treatment, the resin was filtered off, and the obtained filtrate was concentrated under reduced pressure.
This concentrate was dissolved in a small amount of chloroform, applied to a silica gel (100 g) column previously activated with chloroform, and chloroform-methanol (9: 1) 600.
ml, chloroform-methanol-water (65:25:
4) Elution was performed sequentially with 1000 ml. The target fractions were collected from the obtained elution fractions using TLC analysis as an index to obtain 2.57 g (80%) of the target product.
【００２８】本物質は、ＴＬＣ分析（シリカゲルプレー
ト、展開溶媒：クロロホルム−メタノール−水（６５：
２５：４））を行ったところ、沃素及びリンモリブデン
酸による検出で単一のスポットを与え、そのＲｆ値は市
販のジステアロイル−Ｌ−α−グリセロホスホリルコリ
ン（シグマ製）とほぼ一致した。This substance was analyzed by TLC (silica gel plate, developing solvent: chloroform-methanol-water (65:
25: 4)), a single spot was detected by detection with iodine and phosphomolybdic acid, and its Rf value was almost the same as that of commercially available distearoyl-L-α-glycerophosphorylcholine (manufactured by Sigma).
【００２９】（ｂ）１−ステアロイル−２−リノレオイ
ルホスファチジルセリンの合成 Ｌ−セリン８．４ｇ（８０ｍｍｏｌ）を０．１ＭＣａＣ
ｌ2を含む０．１Ｍ酢酸緩衝液２０ｍｌ（ｐＨ５．６）
に溶解後、ホスホリパーゼＤ（１８６単位／ｍｇ，東洋
醸造製）１０ｍｇを加えた。ついで、（ａ）で得られた
１−ステアロイル−２−リノレオイルホスファチジルコ
リン１．７７ｇ（２ｍｍｏｌ）をクロロホルム５０ｍｌ
に溶解したものを加え、３０℃にて約４時間反応させ
た。終了後、反応液に、２Ｎ塩酸２０ｍｌ，クロロホル
ム１９０ｍｌ，メタノール１２０ｍｌ、水２０ｍｌを加
え、分液ロートで分液し、下層を分取して減圧濃縮し
た。得られた濃縮液にクロロホルム−メタノール−０．
１Ｎ塩酸（２：１：０．２）２５０ｍｌを加えて分液
し、下層を分取して減圧濃縮した。この濃縮物を少量の
クロロホルム−メタノール−酢酸（８０：２０：３．
５）に溶解し、あらかじめ同じ溶媒系で活性化したシリ
カゲル（１７０ｇ）カラムにかけ、同じ溶媒系で溶出さ
せた。得られた溶出分画からＴＬＣ分析を指標として目
的画分を集め、目的物１．０５ｇ（５４％）を得た。つ
いで、このものをクロロホルム−メタノール（２：１）
５０ｍｌに溶解し、０．１Ｍ炭酸水素カリウム溶液２８
ｍｌを加えて室温で３０分間攪拌した。終了後、クロロ
ホルムーメタノール（２：１）１３０ｍｌを加えて分液
し、下層を集め、乾固するまで減圧濃縮した。乾固物を
クロロホルムに溶解し、アセトンから再結晶して白色結
晶１．００ｇ（５３％）を得た。(B) Synthesis of 1-stearoyl-2-linoleoylphosphatidylserine 8.4 g (80 mmol) of L-serine was added to 0.1M CaC
0.1M acetate buffer solution 20ml containing l 2 (pH 5.6)
After dissolving in, 10 mg of phospholipase D (186 units / mg, manufactured by Toyo Shuzo) was added. Then, 1.77 g (2 mmol) of 1-stearoyl-2-linoleoylphosphatidylcholine obtained in (a) was added to 50 ml of chloroform.
What was melt | dissolved in was added, and it was made to react at 30 degreeC for about 4 hours. After the completion, 20 ml of 2N hydrochloric acid, 190 ml of chloroform, 120 ml of methanol, and 20 ml of water were added to the reaction solution, and the mixture was separated with a separating funnel. The lower layer was separated and concentrated under reduced pressure. Chloroform-methanol-0.
250 ml of 1N hydrochloric acid (2: 1: 0.2) was added for liquid separation, and the lower layer was separated and concentrated under reduced pressure. A little chloroform-methanol-acetic acid (80: 20: 3.
It was dissolved in 5), applied to a silica gel (170 g) column which had been previously activated with the same solvent system, and eluted with the same solvent system. The target fractions were collected from the obtained elution fractions using TLC analysis as an index to obtain 1.05 g (54%) of the target product. Then, add this to chloroform-methanol (2: 1).
Dissolve in 50 ml, 0.1M potassium hydrogen carbonate solution 28
ml was added and the mixture was stirred at room temperature for 30 minutes. After the completion, 130 ml of chloroform-methanol (2: 1) was added for liquid separation, and the lower layer was collected and concentrated under reduced pressure to dryness. The dried solid was dissolved in chloroform and recrystallized from acetone to obtain 1.00 g (53%) of white crystals.
【００３０】本物質は、ＴＬＣ分析（シリカゲルプレー
ト、展開溶媒：クロロホルム−メタノール−酢酸（８
０：２０：３．５））を行ったところ、沃素及びリンモ
リブデン酸、ニンヒドリン試薬による検出で単一のスポ
ットを与え、そのＲｆ値は市販の牛脳ホスファチジルセ
リン（フナコシ製）とほぼ一致した。1 H-NMR（CDCl3）：δ(ppm) 0.89 (6H), 1.25 (42H), 1.
58 (4H), 2.03 (4H), 2.29 (4H), 2.76 (2H), 3.87 (1
H), 3.95 (2H), 4.11 (2H), 4.36 (2H), 5.14 (1H), 5.
34 (4H), 8.20 (3H).This substance was analyzed by TLC (silica gel plate, developing solvent: chloroform-methanol-acetic acid (8
0: 20: 3.5)), a single spot was obtained by detection with iodine, phosphomolybdic acid and ninhydrin reagent, and its Rf value was almost the same as that of commercially available bovine brain phosphatidylserine (manufactured by Funakoshi). . 1 H-NMR (CDCl 3 ): δ (ppm) 0.89 (6H), 1.25 (42H), 1.
58 (4H), 2.03 (4H), 2.29 (4H), 2.76 (2H), 3.87 (1
H), 3.95 (2H), 4.11 (2H), 4.36 (2H), 5.14 (1H), 5.
34 (4H), 8.20 (3H).
【００３１】その他の不飽和脂肪酸のアシル残基を有す
るホスファチジルセリンも上記と同様にして合成し、同
定した。Other phosphatidylserines having an acyl residue of unsaturated fatty acid were also synthesized and identified in the same manner as above.
【００３２】実施例 ２ （ａ）プロテインキナーゼＣの精製 ラット脳の可溶性画分を、イオン交換クロマトグラフィ
ー（ＤＥＡＥトヨパール−Ｓ）、疎水性クロマトグラフ
ィー(HiLoad 26/10 Phenyl Sepharose High Performanc
e)、ゲルろ過クロマトグラフィー（HiLoad 26/60 Super
dex 200 prep）、ハイドロキシアパタイトクロマトグラ
フィー（Hydoxyapatite type C, 高研）に付することに
より、各アイソザイムの単離、精製を行った。Example 2 (a) Purification of protein kinase C The soluble fraction of rat brain was subjected to ion exchange chromatography (DEAE Toyopearl-S) and hydrophobic chromatography (HiLoad 26/10 Phenyl Sepharose High Performanc).
e), gel filtration chromatography (HiLoad 26/60 Super
dex 200 prep) and hydroxyapatite chromatography (Hydoxyapatite type C, Koken) to isolate and purify each isozyme.
【００３３】 （ｂ）プロテインキナーゼＣ活性化能の測定 マイクロチューブ（１．５ｍｌ）内に、基質溶液〔７０
ｍＭトリス−ＨＣｌ（ｐＨ７．５）（６μｌ）、１５０
ｍＭ ＭｇＣｌ2（３μｌ）、１．５ｍＭ ＣａＣｌ
2（６μｌ）、３ｍｇ／ｍｌ ヒストンＨ１（６μ
ｌ）〕２１μｌ、混合ミセル溶液〔ホスファチジルセリ
ン（トリトンＸ−１００の１０ｍｏｌ％）と１，２−ジ
オレオイルグリセロール（ジオレイン）に、０．３％ト
リトンＸ−１００、２００ｍＭトリス−ＨＣｌ（ｐＨ
７．５）を加え、振とうとインキュベーションを行って
調製〕９μｌ、酵素溶液〔酵素を精製し、透析によりリ
ン酸とＥＤＴＡを除去後、２０ｍＭトリス−ＨＣｌ（ｐ
Ｈ７．５）で希釈〕３０μｌを入れてあらかじめ混合
し、氷冷した。チューブを振とうした後、３０℃のイン
キュベーター中で２分間予備インキュベートした。つい
で、ＡＴＰ溶液｛150μＭ〔γ−32Ｐ〕ＡＴＰ（２ｘ１
０5ｃｐｍ／ｍｍｏｌ）、２０ｍＭトリス−ＨＣｌ（ｐ
Ｈ７．５）を添加｝３０μｌを加えて振とうして反応を
開始させ、３０℃で１５分間インキュベートした。その
後、氷冷した２５％トリクロロ酢酸溶液１００μｌを加
えて振とうし、反応を停止させた。(B) Measurement of Protein Kinase C Activating Ability The substrate solution [70
mM Tris-HCl (pH 7.5) (6 μl), 150
mM MgCl 2 (3 μl), 1.5 mM CaCl
2 (6 μl), 3 mg / ml histone H1 (6 μl
l)], 21 μl, mixed micelle solution [phosphatidylserine (10 mol% of Triton X-100) and 1,2-dioleoylglycerol (diolein), 0.3% Triton X-100, 200 mM Tris-HCl (pH)
7.5) was added, and the mixture was shaken and incubated to prepare] 9 μl, enzyme solution [enzyme was purified, phosphate and EDTA were removed by dialysis, and 20 mM Tris-HCl (p
Diluted with H7.5)] 30 μl was added and mixed in advance, and cooled on ice. After shaking the tube, it was preincubated for 2 minutes in an incubator at 30 ° C. Then, ATP solution {150 μM [γ- 32 P] ATP (2x1
0 5 cpm / mmol), 20 mM Tris-HCl (p
H7.5) was added} 30 μl was added and shaken to start the reaction, and the mixture was incubated at 30 ° C. for 15 minutes. Then, 100 μl of ice-cooled 25% trichloroacetic acid solution was added and shaken to stop the reaction.
【００３４】反応停止後、チューブ内の全量１９０μｌ
のうち１２５μｌを、２．５ｘ２．５ｃｍの正方形に切
ったｐｈｏｓｐｈｏｃｅｌｌｕｌｏｓｅ ｄｉｓｋ（ワ
ットマン Ｐ８１）に適下し、リン酸化されたヒストン
Ｈ１を吸着させた。このイオン交換ろ紙を、５％酢酸溶
液中で振とうしながら洗浄し、遊離ＡＴＰを洗い流し
た。この操作を１０分ｘ２回行った。洗浄し終わったイ
オン交換ろ紙を、そのままＷｈｅａｔｏｎのＯｍｎｉ−
ｖｉａｌの中に入れた。Ａｔｏｍｌｉｇｈｔ（ＮＥＮ，
ＮＥＦ−９６８）を２．６ｍｌ加え、放射能を測定し
た。After the reaction was stopped, the total volume in the tube was 190 μl
125 μl of this was applied to a phosphocellulose disk (Whatman P81) cut into 2.5 × 2.5 cm squares to adsorb phosphorylated histone H1. The ion-exchange filter paper was washed in a 5% acetic acid solution with shaking to wash out free ATP. This operation was performed twice for 10 minutes. The washed ion-exchange filter paper is used as it is for Wheaton's Omni-
I put it in the vial. Atomlight (NEN,
2.6 ml of NEF-968) was added and the radioactivity was measured.
【００３５】プロテインキナーゼＣ活性は、アッセイチ
ューブ１本（反応混合物９０μｌ）あたり１分間で、ヒ
ストンＨ１に転移されたリン酸のモル数で表した（単
位：ｐｍｏｌ／ｍｉｎ／９０μｌ）。なお、ホスファチ
ジルセリンとジオレインを加えないでトリトンＸ−１０
０のみのリピド溶液を使用した場合をブランクとして、
全ての測定値よりこのブランクの値を差し引いて活性値
を計算した。種々の濃度のジオレインを用いて、ジオレ
インによるプロテインキナーゼＣ活性化のＥＤ50を算出
した。The protein kinase C activity was expressed as the number of moles of phosphoric acid transferred to histone H1 per assay tube (reaction mixture 90 μl) for 1 minute (unit: pmol / min / 90 μl). In addition, Triton X-10 was prepared without adding phosphatidylserine and diolein.
When the lipid solution containing only 0 was used as a blank,
The activity value was calculated by subtracting the blank value from all the measured values. The ED 50 for protein kinase C activation by diolein was calculated using various concentrations of diolein.
【００３６】（ｃ）測定結果 プロテインキナーゼＣ活性化能の測定結果を第１図〜第
３図に示す。これらの結果は、プロテインキナーゼＣア
イソザイムαに対しては、飽和型ホスファチジルコリン
及び２位にオレイン酸残基を有するホスファチジルセリ
ンの活性が弱く、他のリノール酸、リノレン酸、アラキ
ドン酸、イコサペンタエン酸、ドコサヘキサエン酸残基
を有するものがに強い活性を有することを示している。
一方、アイソザイムβとγについては、飽和型、２位が
オレイン酸及び、意外にも、イコサペンタエン酸残基を
有するものは弱い活性しか示さず、リノール酸、リノレ
ン酸、アラキドン酸、ドコサヘキサエン酸残基を有する
ものに強い活性が認められた。(C) Measurement Results The measurement results of protein kinase C activating ability are shown in FIGS. 1 to 3. These results show that the activity of saturated phosphatidylcholine and phosphatidylserine having an oleic acid residue at the 2-position is weak with respect to protein kinase C isozyme α, and other linoleic acid, linolenic acid, arachidonic acid, icosapentaenoic acid, docosahexaenoic acid It shows that those having an acid residue have strong activity.
On the other hand, with respect to isozymes β and γ, saturated type, oleic acid at the 2-position and, surprisingly, those having an icosapentaenoic acid residue show only weak activity, and linoleic acid, linolenic acid, arachidonic acid, docosahexaenoic acid residue Strong activity was observed for those with.
【００３７】[0037]
【発明の効果】本発明のプロテインキナーゼＣ活性化剤
は、強い活性化能を有すると共に、天然の牛脳ホスファ
チジルセリンを用いる場合のような不純物による副作用
の心配はない。本発明のプロテインキナーゼＣ活性化剤
は、中枢神経障害（記憶障害等）を伴う老人性痴呆症、
特にアルツハイマー病の治療剤として期待される。INDUSTRIAL APPLICABILITY The protein kinase C activator of the present invention has a strong activating ability and is free from side effects due to impurities as in the case of using natural bovine brain phosphatidylserine. The protein kinase C activator of the present invention comprises senile dementia with central nervous system disorders (memory disorders, etc.),
In particular, it is expected as a therapeutic agent for Alzheimer's disease.
【図１】各種ホスファチジルセリン誘導体を用いた、ジ
オレインによるプロテインキナーゼＣアイソザイムα活
性化におけるＥＤ50を示すグラフである。FIG. 1 is a graph showing the ED 50 in protein kinase C isozyme α activation by diolein using various phosphatidylserine derivatives.
【図２】各種ホスファチジルセリン誘導体を用いた、ジ
オレインによるプロテインキナーゼＣアイソザイムβ活
性化におけるＥＤ50を示すグラフである。FIG. 2 is a graph showing ED 50 in protein kinase C isozyme β activation by diolein using various phosphatidylserine derivatives.
【図３】各種ホスファチジルセリン誘導体を用いた、ジ
オレインによるプロテインキナーゼＣアイソザイムγ活
性化におけるＥＤ50を示すグラフである。FIG. 3 is a graph showing ED 50 in protein kinase C isozyme γ activation by diolein using various phosphatidylserine derivatives.
１８：１はオレイン酸、１８：２はリノール酸、１８：
３はリノレン酸、２０：４はアラキドン酸、２０：５は
イコサペンタエン酸、２２：６はドコサヘキサエン酸を
示し、ＤＧはジオレインを示す。18: 1 is oleic acid, 18: 2 is linoleic acid, and 18:
3 is linolenic acid, 20: 4 is arachidonic acid, 20: 5 is icosapentaenoic acid, 22: 6 is docosahexaenoic acid, and DG is diolein.
Claims (2)
テアリン酸のアシル残基を表わし、Ｒ2はリノール酸、
リノレン酸、アラキドン酸、またはドコサヘキサエン酸
のアシル残基を表わす）で表わされるホスファチジルセ
リン誘導体又はその薬学上許容しうる塩を有効成分とす
るプロテインキナーゼＣアイソザイムβまたはγの活性
化剤。1. The following general formula: (In the formula, R 1 represents an acyl residue of myristic acid, palmitic acid, or stearic acid, R 2 represents linoleic acid,
An activator of protein kinase C isozyme β or γ containing a phosphatidylserine derivative represented by linolenic acid, arachidonic acid, or an acyl residue of docosahexaenoic acid) or a pharmaceutically acceptable salt thereof as an active ingredient.
肪酸のアシル残基を表わす）で表わされるジアシルグリ
セロールをさらに含有することを特徴とする請求項１記
載の活性化剤。2. The following general formula: The activator according to claim 1, further comprising diacylglycerol represented by the formula: wherein R 3 and R 4 independently represent an acyl residue of a fatty acid having 12 to 22 carbon atoms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5090522A JPH06279311A (en) | 1993-03-26 | 1993-03-26 | Activation agent for protein kinase c isozyme |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5090522A JPH06279311A (en) | 1993-03-26 | 1993-03-26 | Activation agent for protein kinase c isozyme |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06279311A true JPH06279311A (en) | 1994-10-04 |
Family
ID=14000780
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5090522A Withdrawn JPH06279311A (en) | 1993-03-26 | 1993-03-26 | Activation agent for protein kinase c isozyme |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06279311A (en) |
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| EP0711559A3 (en) * | 1994-11-08 | 1997-01-15 | Yakult Honsha Kk | Use of phosphatidylserines for the manufacture of a medicament for improving cerebration |
| WO1999013911A1 (en) * | 1997-09-12 | 1999-03-25 | Daiichi Pharmaceutical Co., Ltd. | Nootropic agent |
| US5965413A (en) * | 1995-11-08 | 1999-10-12 | Kabushiki Kaisha Yakult Honsha | Process for producing phosphatidylserines having long chain unsaturated fatty acid as side chain |
| WO2000053218A1 (en) * | 1999-03-09 | 2000-09-14 | The University Court Of The University Of Glasgow | Neurodegenerative disorder related gene |
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1993
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