JP2665766B2 - Memory enhancer - Google Patents
Memory enhancerInfo
- Publication number
- JP2665766B2 JP2665766B2 JP63103321A JP10332188A JP2665766B2 JP 2665766 B2 JP2665766 B2 JP 2665766B2 JP 63103321 A JP63103321 A JP 63103321A JP 10332188 A JP10332188 A JP 10332188A JP 2665766 B2 JP2665766 B2 JP 2665766B2
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- Prior art keywords
- asp
- memory
- tyr
- phe
- trp
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Description
【発明の詳細な説明】 産業上の利用分野 本発明は次式： Pyr−Ｘ−Asp−Tyr（SO3H）−Ｙ−Gly−Trp−Ｚ−Asp −Phe−NH2 （式中、ＸはGlnまたは単に結合部を示し、ＹはThrまた
はLeuを示し、ＺはMetまたはNleを示す）で表わされる
ペプチド類（以下単に本ペプチドという）またはその製
薬上許容される塩を有効成分とする新規な記憶力増強剤
に関する。FIELD OF THE DETAILED DESCRIPTION OF THE INVENTION Industry invention the following formula: Pyr-X-Asp-Tyr (SO 3 H) -Y-Gly-Trp-Z-Asp -Phe-NH 2 ( wherein, X Represents a Gln or simply a binding site, Y represents Thr or Leu, Z represents Met or Nle) (hereinafter simply referred to as the present peptide) or a pharmaceutically acceptable salt thereof as an active ingredient It relates to a novel memory enhancer.
従来技術 本発明が取り扱うペプチドは公知の化合物であり、バ
イオケミカル・ファーマコロジー（Biochemical Pharma
cology 1103−1107,34（７）,1985M.Fujimoto et al）
に開示されている。藤本等は膵臓や脳に分布するコレシ
ストキニン（以下CCKという）受容体との親和性を各ペ
プチドについて研究している。しかし、これらペプチド
に記憶力増進作用があるという異は記述もなく、示唆も
されていない。2. Description of the Related Art Peptides handled by the present invention are known compounds, and are known from Biochemical Pharmacology.
cology 1103-1107,34 (7), 1985M. Fujimoto et al)
Is disclosed. Fujimoto et al. Have studied the affinity of each peptide for the cholecystokinin (CCK) receptor distributed in the pancreas and brain. However, there is no description or suggestion that these peptides have a memory-enhancing effect.
一方、CCKには分子の大きいものから小さいものまで
いろいろあるが、脳には８個のアミノ酸からなるペプチ
ドが多く存在し、Ｃ末端から７番目のアミノ酸に硫酸基
のついているのが特徴である。これは略してCCK−８と
呼ばれているが、伊藤等は各種の実験から、CCK−８に
は学習・記憶増進効果がある事をつきとめている（Pept
ides 7,105−110（1986）;Drug Devel.Res.7,269−276
（1986）;Can.j.Phiol.Pharmacol 64,745−747（198
6）;ibid.65,2260−2264（1987）;Drug Rev.Res.12,63
−70（1988））。CCK, on the other hand, has a variety of molecules, from large to small, but has many peptides consisting of eight amino acids in the brain and is characterized by a sulfate group at the seventh amino acid from the C-terminal. . This is called CCK-8 for short, but Ito et al. Have found from various experiments that CCK-8 has a learning and memory enhancing effect (Pept
ides 7, 105-110 (1986); Drug Devel. Res. 7, 269-276.
(1986); Can.j.Phiol.Pharmacol 64,745-747 (198
6); ibid. 65,2260-2264 (1987); Drug Rev. Res. 12, 63
-70 (1988)).
特公昭第60−41052号にはセルレインの向精神薬、特
に分裂病に効果のあることが記載されている。Japanese Patent Publication No. 60-41052 describes that cerulein is effective for psychotropic drugs, especially schizophrenia.
発明が解決する課題 近年、平均寿命が年々のびるに従い、老人福祉が大き
な社会問題となっている。特に、老人の記憶力減退に伴
った問題が多く、記憶力増進剤または記憶力減退防止剤
の開発が強く望まれている。Problems to be Solved by the Invention In recent years, as the average life expectancy increases, welfare for the elderly has become a major social problem. In particular, there are many problems associated with memory loss of elderly people, and there is a strong demand for the development of a memory enhancer or an agent for preventing memory loss.
課題を解決する手段 本発明者らは以上の点に鑑み、鋭意研究を重ねた結
果、次式： Pyr−Ｘ−Asp−Tyr（SO3H）−Ｙ−Gly−Trp−Ｚ−Asp −Phe−NH2 （式中、Ｘ、Ｙ、およびＺは前記と同意義）で表わされ
る本ペプチドまたはその製薬上許容される塩が記憶力の
保持を延長すると共に記憶の喪失を防止する効果をもつ
を見出し、本発明を完成した。本発明者らの研究によれ
ば、本ペプチドは同作用を有するCCK−８と比較して、
約10倍の効力を示す。Means the inventors for solving the problems In view of the above, the results of extensive studies, the following formula: Pyr-X-Asp-Tyr (SO 3 H) -Y-Gly-Trp-Z-Asp -Phe -NH 2 (wherein, X, Y, and Z are the same as defined) to have the effect of preventing the loss of memory with acceptable salt present peptide or a pharmaceutically represented by to extend the memory retention force Heading, the present invention has been completed. According to the study of the present inventors, the present peptide is compared with CCK-8 having the same action,
It shows about 10 times the efficacy.
本発明において、アミノ酸、ペプチド、活性基等に関
して略号で表示する場合、IUPACまたは当該分野の慣用
記号に従った。以下に主なものを例示する。In the present invention, when abbreviations are used for amino acids, peptides, active groups and the like, IUPAC or conventional symbols in the art are used. The main ones are exemplified below.
Asp:アスパラギン酸 Gln:グルタミン Gly:グリシン Leu:ロイシン Met:メチオニン Nle:ノルロイシン Phe:フェニルアラニン Pyr:ピログルタミン酸 Thr:スレオニン Trp:トリプトファン Tyr:チロシン 以下に本ペプチドのいくつかを例示するが、本発明は
これらに限定されるものではない。Asp: aspartic acid Gln: glutamine Gly: glycine Leu: leucine Met: methionine Nle: norleucine Phe: phenylalanine Pyr: pyroglutamic acid Thr: threonine Trp: tryptophan Tyr: tyrosine It is not limited to these.
化合物（１）（セルレイン）： Pyr−Gln−Asp−Tyr（SO3H）−Thr−Gly−Trp−Met −Asp−Phe−NH2 化合物（２）： Pry−Asp−Tyr（SO3H）−Thr−Gly−Trp−Met−Asp −Phe−NH2 化合物（３）： Pyr−Gln−Asp−Tyr（SO3H）−Leu−Gly−Trp −Nle−Asp−Phe−NH2 CCK−8: Ｈ−Asp−Tyr（SO3H）−Met−Gly−Trp−Met−Asp−Phe −NH2 本ペプチドは製薬上許容される塩、例えばナトリウ
ム、カリウム等のアルカリ金属塩、カルシウム等のアル
カリ土類金属塩、ジエチルアミン、トリエチルアミン等
のアミン塩またはアンモニアとのアンモニウム塩として
も良い。Compound (1) (caerulein): Pyr-Gln-Asp- Tyr (SO 3 H) -Thr-Gly-Trp-Met -Asp-Phe-NH 2 Compound (2): Pry-Asp- Tyr (SO 3 H) -Thr-Gly-Trp-Met- Asp -Phe-NH 2 compound (3): Pyr-Gln- Asp-Tyr (SO 3 H) -Leu-Gly-Trp -Nle-Asp-Phe-NH 2 CCK-8 : H-Asp-Tyr (SO 3 H) -Met-Gly-Trp-Met-Asp-Phe -NH 2 present salt peptides are pharmaceutically acceptable, such as sodium, alkali metal salts such as potassium, an alkali such as calcium An earth metal salt, an amine salt such as diethylamine or triethylamine, or an ammonium salt with ammonia may be used.
本ペプチドはそれぞれ単独または混合物で用いること
ができる。製剤化にあたっては、非経口投与形態が好ま
しく、常法に従って注射剤、座剤、貼付剤、鼻腔内スプ
レー等に製剤化すれば良く、要すれば、増量剤、賦形
剤、溶解助剤、安定化剤、防腐剤、局麻剤等を添加し得
るのは当然であるが、更に、本ペプチドの効力を低下さ
せない限り他の薬剤も添加できる。The present peptides can be used alone or in a mixture. In formulating, a parenteral administration form is preferable, and it may be formulated into an injection, a suppository, a patch, an intranasal spray, etc. according to a conventional method, and if necessary, a bulking agent, an excipient, a dissolution aid, Naturally, stabilizers, preservatives, local anesthetics and the like can be added, but other agents can be added as long as the efficacy of the present peptide is not reduced.
本ペプチドは非常に低毒性などで、かなり大量に使用
可能である。人体への投与量は、性別、年齢、症状、病
歴、投与方法によって変化するので一概に規定できない
が、通常、0.01〜10μg/kg体重、より好ましくは0.05〜
５μg/kg体重を毎週１回〜２回投与すればよい。This peptide has very low toxicity and can be used in a considerably large amount. The dose to the human body can not be specified unconditionally because it varies depending on gender, age, symptoms, medical history, administration method, but usually 0.01 to 10 μg / kg body weight, more preferably 0.05 to
5 μg / kg body weight may be administered once or twice weekly.
本ペプチドは上記の使用方法で、例えば、脳外傷によ
って生じた記憶喪失の治療、パーキンソン病やハンチン
トン病等の脳疾患や過度のストレス状態における記憶障
害の改善、老年期精神活動減退の改善、脳外科手術によ
って生じる脳機能障害の予防等に臨床的効果が期待され
る。The peptide can be used in the above-described manner to treat, for example, treatment of memory loss caused by brain trauma, improvement of memory disorders in brain diseases such as Parkinson's disease and Huntington's disease and excessive stress, improvement of senile mental activity decline, brain surgery It is expected to have clinical effects in preventing cerebral dysfunction caused by surgery.
以下に実施例を示し本発明をさらに詳しく説明する
が、これらは何等本発明を限定するものではない。Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention in any way.
実施例 １ （受動的回避反応） ウィスター系雄性ラット（体重約220g）を25±１℃、
12時間毎の明暗条件（点灯：午前７時）の下で飼育し、
その間摂食（標準ラット用ビスケット）および水は自由
に与えた。以下の実験は午前９時〜午後３時の間に行な
った。Example 1 (Passive avoidance reaction) Male Wistar rats (body weight: about 220 g) were subjected to 25 ± 1 ° C.
It is bred under light and dark conditions every 12 hours (lighting: 7:00 am)
During that time, food (standard rat biscuits) and water were provided ad libitum. The following experiments were performed between 9 am and 3 pm
受動的回避行動は一試行学習法によって調べた。うす
暗い防音室内で実験を行なった。装置は黒色壁の暗い箱
と、その一面に明るい走路をつけたものである。暗箱の
床にはラットの足に電気ショック（Foot Shck:以下、FS
という）を与えられるようにグリッドを配した。グリッ
ドを配した部屋を暗箱とし、走路の中央部60cm上方に60
Wの電球を取り付けた。以上の装置を用いて、受動的回
避学習の一回試行をエーダーとドゥ・ウイード（Ader a
nd de Wied［1972］）の方法に従って観察した。ラット
を暗箱に背を向けるように層等上に置き、そのまま暗箱
に入れるという順応訓練を実験の第１日に一回、同訓練
を翌日に３回行なった。３回目の訓練終了後直ちに、ラ
ットに強制的電気ショック（0.2mA,2秒間）を一回与え
た。この学習訓練の後、ラットを装置から取出した。学
習訓練終了後24時間と48時間目に記憶保持をテストし
た。ラットを走路上に置き、ラットが暗室に入るまでの
時間（反応潜時）を最大300秒まで測定した。Passive avoidance behavior was examined by one-trial learning. The experiment was performed in a dark, soundproof room. The device consists of a dark box with black walls and a bright runway on one side. Electric shock (Foot Shck: FS)
The grid was arranged so that it could be given. The room where the grid is arranged is used as a dark box, and 60 cm above the center of the runway 60 cm
W light bulb was attached. Using the above device, one trial of passive avoidance learning was performed by Eder and De Weed (Ader a
nd de Wied [1972]). The rats were placed on a layer or the like with their backs turned to the dark box, and the adaptation training was performed once on the first day of the experiment and three times on the next day. Immediately after the end of the third training, the rats were given one forced electric shock (0.2 mA, 2 seconds). After this training, the rats were removed from the device. Memory retention was tested 24 and 48 hours after completion of the training. The rats were placed on the runway, and the time until the rats entered the dark room (reaction latency) was measured up to 300 seconds.
ラットの記憶を喪失させるために、FS直後、両耳に取
り付けた金属クリップを介して電流を通じ（60mA,0.4秒
間）、電気痙攣ショック（Electroconvulsive shock:以
下、ECSと言う）を与えた。Immediately after FS, an electroconvulsive shock (ECS) was given immediately after FS through a metal clip attached to both ears (60 mA, 0.4 seconds) in order to cause the rats to lose memory.
薬剤は生理食塩水に溶解して0.1ml/100g体重宛でECS
直後に皮下投与した。対照群にも同量の生理食塩水を皮
下投与した。反応潜時の値は秒で示し、平均反応潜時と
共にカッコ内に25％〜75％の分布値を表１に示した。
尚、実験動物は一回のみ、実験に使用した。Drugs are dissolved in physiological saline and ECS to 0.1 ml / 100 g body weight
Immediately after, it was administered subcutaneously. The same amount of physiological saline was subcutaneously administered to the control group. The values of the reaction latencies are shown in seconds, and the distribution values of 25% to 75% in parentheses are shown in Table 1 together with the average reaction latencies.
The experimental animal was used only once for the experiment.
尚、本試験および以下の諸実施例で用いる化合物は以
下の通りである。The compounds used in this test and the following examples are as follows.
化合物（１）（セルレイン）： Pyr−Gln−Asp−Tyr（SO3H）−Thr−Gly−Trp−Met −Asp−Phe−NH2 化合物（２）： Pry−Asp−Tyr（SO3H）−Thr−Gly−Trp−Met−Asp −Phe−NH2 化合物（３）： Pyr−Gln−Asp−Tyr（SO3H）−Leu−Gly−Trp −Nle−Asp−Phe−NH2 対照化合物（CCK−８）： Ｈ−Asp−Tyr（SO3H）−Met−Gly−Trp−Met−Asp−Phe −NH2 効果 表１の結果から明らかな様に、本化合物１〜３はいず
れも、CCK−８と比較して約10倍もの効果を示し、記憶
力減退を防止する効果が確認された。また、統計結果を
表１（附）に示した。Compound (1) (caerulein): Pyr-Gln-Asp- Tyr (SO 3 H) -Thr-Gly-Trp-Met -Asp-Phe-NH 2 Compound (2): Pry-Asp- Tyr (SO 3 H) -Thr-Gly-Trp-Met- Asp -Phe-NH 2 compound (3): Pyr-Gln- Asp-Tyr (SO 3 H) -Leu-Gly-Trp -Nle-Asp-Phe-NH 2 control compound ( CCK-8): H-Asp -Tyr (sO 3 H) -Met-Gly-Trp-Met-Asp-Phe -NH 2 effect table 1 as is apparent from the results, both the compounds 1-3, The effect was about 10 times higher than that of CCK-8, and the effect of preventing memory loss was confirmed. The statistical results are shown in Table 1 (Appendix).
実施例 ２ （能動的回避反応） ウィスター系雄性ラット（体重約220g）を25±１℃、
12時間毎の明暗条件（点灯：午前７時）の下で飼育し、
その間摂食（標準ラット用ビスケット）および水は自由
に与えた。以下の実験は午前９時〜午後３時の間に行な
った。 Example 2 (Active avoidance reaction) Male Wistar rats (body weight: about 220 g) were treated at 25 ± 1 ° C.
It is bred under light and dark conditions every 12 hours (lighting: 7:00 am)
During that time, food (standard rat biscuits) and water were provided ad libitum. The following experiments were performed between 9 am and 3 pm
受動的回避行動はガムズ（Gamzu,1985）の方法に準じ
たプラットホーム型による実験を行なった。一連の試行
を開始する10分前にラットを実験箱に入れて慣らし、そ
の後プラットホーム上に置いた。プラットホーム（18×
10cm）は実験箱（40×35×40cm）の床上11cmにあり、箱
の隅に取り付けられた。各試行の開始毎に条件刺激（Co
nditioning stimulus:以下CSという）の為にブザーを鳴
らし、ラットをプラットホームからグリッドを配した床
に降した。CSは15秒間行ない、次いで2mAの電流を15秒
間通じてFSを与えた。ラットはプラットホームへ飛び乗
る事によりこれを回避し得た。ショック終了から次ぎの
試行までの15秒間を安全期間とした。これを１試行とし
て、５試行を１セクションとした。各セッションは約４
時間の間隔をあけ、朝・夕に各一回ずつ行なった。第２
セッション終了後（訓練日）直ちに全てのラットに所定
量の薬剤または生理食塩水を皮下投与した。被検群には
薬剤を生理食塩水に溶解して0.1ml/100g体重宛を、対照
群には同量の生理食塩水を投与した。For passive avoidance behavior, we performed a platform-type experiment based on the method of Gamzu (Gamzu, 1985). Ten minutes before the start of the series of trials, rats were placed in the laboratory box to habituate and then placed on the platform. Platform (18 ×
10 cm) was 11 cm above the floor of the laboratory box (40 x 35 x 40 cm) and was mounted in the corner of the box. Conditional stimuli (Co
The buzzer sounded for nditioning stimulus (hereinafter CS) and the rat was dropped from the platform to the floor with the grid. CS was performed for 15 seconds, then passed 2 mA of current for 15 seconds to give FS. Rats could avoid this by jumping onto the platform. The safety period was 15 seconds from the end of the shock to the next trial. This was taken as one trial, and five trials were taken as one section. Each session is about 4
The test was performed once each in the morning and evening with a time interval. Second
Immediately after the end of the session (training day), all rats were given a predetermined amount of a drug or physiological saline subcutaneously. The test group was administered with the drug dissolved in physiological saline at a dose of 0.1 ml / 100 g body weight, and the control group received the same amount of physiological saline.
FSを除いた以外は同様の２セッションを翌日（第１
日）、第５日、10日、15日目にも繰り返し行なった。各
セッション毎に回避行動を取った回数を数え、４日間に
取った回避行動の平均値を表２に記した。統計処理はダ
ンカン（Dunkan）の方法で行なった。Except for FS, the same two sessions were held the next day (No. 1
), The fifth, the tenth and the fifteenth day. The number of avoidance actions taken for each session was counted, and the average value of the avoidance actions taken for four days is shown in Table 2. Statistical processing was performed by the method of Duncan.
効果 表２の結果から明らかな様に、本化合物１〜３はいず
れも、CCK−８と比較して約10倍もの効果を示し、記憶
力を増強する効果の極めて高い薬剤であることが確認さ
れた。Effect As is clear from the results in Table 2, all of the present compounds 1 to 3 show about 10 times the effect as compared with CCK-8, and it is confirmed that the compounds are extremely effective in enhancing the memory ability. Was.
実施例３（毒性試験） （被検化合物） 化合物２および３をそれぞれ0.040mg/mlの濃度で生理
食塩水に溶解し、溶解後40分以内に投与した。 Example 3 (Toxicity test) (Test compounds) Compounds 2 and 3 were each dissolved in physiological saline at a concentration of 0.040 mg / ml, and administered within 40 minutes after dissolution.
（試験動物および群の構成） SLC:ウィスター系ラット雌雄各25匹を４週齢で購入し、
雌雄各５匹を入荷時検疫した。残り雌雄各20匹を４日間
予備飼育した後、無作為に雌雄各９匹の２群に分けた。
さらに１日間の馴化飼育後、被検化合物を投与した。投
与時のラットの体重は99.1±1.2g、雌82.4±0.8gであっ
た。(Composition of test animals and groups) SLC: 25 male and female Wistar rats were purchased at the age of 4 weeks,
Five males and 5 females were quarantined at the time of arrival. After the remaining 20 males and 20 males were preliminarily reared for 4 days, they were randomly divided into two groups of 9 males and 9 females.
After acclimated breeding for one day, the test compound was administered. At the time of administration, the rats weighed 99.1 ± 1.2 g and females 82.4 ± 0.8 g.
（投与量および投与方法） 実施例１および２で確認した、化合物２および３の皮
下投与時の有効量が0.01μg/kgだったので、その１万倍
に相当する0.1mg/kgを投与量として設定した。投与日に
体重を測定し、個々の動物の体重あたりの投与容量を換
算し、ラット背部皮下に注射した。(Dosage and Administration Method) Since the effective amount of subcutaneous administration of Compounds 2 and 3 confirmed in Examples 1 and 2 was 0.01 μg / kg, 0.1 mg / kg corresponding to 10,000 times the dose was administered. Was set as The body weight was measured on the day of administration, and the dose volume per body weight of each animal was converted and injected subcutaneously on the back of the rat.
実験成績および結論 第14日間の観察期間で、いずれの群においても一般状
態の変化は見られず、良好な体重増加が観察された。ま
た、解倍して病理所見を調べたが、肉眼所見および組織
学的所見になんら異常は認められなかった。Experimental Results and Conclusion During the observation period on the 14th day, no change in general condition was observed in any of the groups, and favorable weight gain was observed. In addition, the cells were magnified and examined for pathological findings. No abnormalities were found in the gross findings and histological findings.
従って、化合物２および３の毒性量は0.1mg/kgより大
であると考えられ、極めて安全な薬剤と結論される。Therefore, the toxic dose of Compounds 2 and 3 is considered to be greater than 0.1 mg / kg, concluding that it is a very safe drug.
尚、化合物１のセルレインは既に人体にも投与され、
安全性は確認されている（特公昭第60−41052号）。The compound 1 caerulein has already been administered to the human body,
Safety has been confirmed (Japanese Patent Publication No. 60-41052).
実施例４ 化合物１のジエチルアミン塩 0.3mg 塩化ナトリウム 90 mg 注射用蒸留水を加えて全量を10mlとする。上記組成物
を完全に溶解したのち、無菌濾過してアンプル10本に分
注して注射剤とする。Example 4 Diethylamine salt of compound 1 0.3 mg Sodium chloride 90 mg Distilled water for injection is added to make the total volume 10 ml. After the above composition is completely dissolved, the composition is aseptically filtered and dispensed into 10 ampoules to give an injection.
実施例５ 化合物２のトリエチルアミン塩 6mg キシロカイン 250mg リン酸緩衝液 100ml 上記組成物を完全に溶解したのち、実施例４と同様に
処理して注射剤100アンプルを得る。Example 5 Triethylamine salt of Compound 2 6 mg Xylocaine 250 mg Phosphate buffer 100 ml After the above composition was completely dissolved, the same treatment as in Example 4 was carried out to obtain 100 ampules of an injection.
実施例６ 化合物３のトリス・ジエチルアミン塩（50mg）を流動
パラフィン（25g）に撹拌溶解して、これに加温溶解し
たカカオ脂（500g）を加えて撹拌分散させた後、座剤50
0個に成形する。Example 6 Tris-diethylamine salt (50 mg) of Compound 3 was stirred and dissolved in liquid paraffin (25 g), and cocoa butter (500 g) dissolved by heating was added thereto, followed by stirring and dispersion.
Form into 0 pieces.
Claims (1)
はLeuを示し、ＺはMetまたはNleを示す）で表わされる
ペプチドまたはその製薬上許容される塩を有効成分とす
る記憶力増強剤。1. A following formula: Pyr-X-Asp-Tyr ( SO 3 H) -Y-Gly-Trp-Z-Asp -Phe-NH 2 ( wherein, X represents a Gln or simply coupling portion, Y Represents Thr or Leu, and Z represents Met or Nle) or a pharmaceutically acceptable salt thereof, as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63103321A JP2665766B2 (en) | 1988-04-26 | 1988-04-26 | Memory enhancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63103321A JP2665766B2 (en) | 1988-04-26 | 1988-04-26 | Memory enhancer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01275533A JPH01275533A (en) | 1989-11-06 |
| JP2665766B2 true JP2665766B2 (en) | 1997-10-22 |
Family
ID=14350932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63103321A Expired - Fee Related JP2665766B2 (en) | 1988-04-26 | 1988-04-26 | Memory enhancer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2665766B2 (en) |
-
1988
- 1988-04-26 JP JP63103321A patent/JP2665766B2/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| Ｂｉｏｃｈｅｍ．Ｐｈａｒｍａｃｏｌ．，Ｖｏｌ．３４，Ｎｏ．７ （１９８５） Ｐ．１１０３−１１０７ |
| Ｃａｎ．Ｊ．Ｐｈｙｓｉｏｌ．Ｐｈａｒｍａｃｏｌ．，Ｖｏｌ．６５ （１９８７） Ｐ．２２６０−２２６４ |
| Ｐｅｐｔｉｄｅｓ，Ｖｏｌ．７，（１９８６） Ｐ．１０５−１１０ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01275533A (en) | 1989-11-06 |
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| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |