CN1154656C - 一类记忆增强肽和它们的用途 - Google Patents

一类记忆增强肽和它们的用途 Download PDF

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CN1154656C
CN1154656C CNB001168762A CN00116876A CN1154656C CN 1154656 C CN1154656 C CN 1154656C CN B001168762 A CNB001168762 A CN B001168762A CN 00116876 A CN00116876 A CN 00116876A CN 1154656 C CN1154656 C CN 1154656C
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memory
improving
application
improving peptides
peptides
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CN1331083A (zh
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杜雨苍
沈金焕
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Zhongkeyingtai Biotech Co., Ltd., Shanghai
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Zhongkeyingtai Biotech Co Ltd Shanghai
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Priority to CNB001168762A priority Critical patent/CN1154656C/zh
Priority to JP2002507844A priority patent/JP4372417B2/ja
Priority to EP01949207A priority patent/EP1300416B1/en
Priority to US10/311,858 priority patent/US7119063B2/en
Priority to PCT/CN2001/000875 priority patent/WO2002002592A1/zh
Priority to AU2001270451A priority patent/AU2001270451A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

本发明对记忆增强肽通过化学合成多肽结构改进，通过动物试验证明该类化合物具有较明显的生理活性有望对改善成年人智力障碍或健忘症并促进未成年儿童的智力发育，甚至可为老年痴呆患者的临床药物。

Description

一类记忆增强肽和它们的用途
(一)技术领域
本发明涉及多肽及它的类似物的合成，更具体的说是记忆增强肽和它的类似物的合成与应用。
(二)背景技术
有关垂体后叶加压素(AVP)等多肽能影响动物的记忆过程，而对学习未发现有明显作用已经有了报导。由于AVP是一类增加血压和抗利尿的体内激素，因此它不适合用于增强记忆方面的临床治病，为此我们在发明专利记忆增强肽及其应用(ZL93112493.X)的基础上，继续对其结构进行改造，药理试验，希望能改进现有专利存在的缺陷，寻找出结构简单、生产便利、药理作用更强的新记忆增强肽，能在临床上对未成年儿童智力发育，改善成年人智力障碍或健忘症，促进人的记忆功能。
(三)发明内容
本发明目的是提供一类能增加记忆的记忆增强肽，促进未成年儿童的智力发育，改善成年人智力障碍或健忘症，甚至作为对老年性痴呆患者病情的改善的药物。
本发明结合生物活性的测定设计出一类具有记忆、学习功能的新化合物，它的结构通式如下：
X为Ala，Leu；Ile；Cys；Phe；Tyr；Val；
R1为PyroGlu；H
R2为S-S-(CH3)3或S-(CH3)3。
本发明可通过固相多肽合成法或液相多肽合成法逐步合成制得，以下是合成步骤：
(I)肽的合成
反应过夜。
Figure C0011687600044
Figure C0011687600045
反应过夜。
Figure C0011687600047
2、Asn·Cys(Bu′)·Pro·Arg的化学合成
Figure C0011687600049
(1)TFA/CH2Cl2(1∶1)30分钟
(2)Et3N/CH2Cl2
                  DDC/BTA/CH2Cl2
                  反应过程
同上1，2处理。
Figure C0011687600052
Figure C0011687600053
本发明所合成的记忆增强肽的药理试验采用分成给药组、对照组及模型组三组动物分别给记忆肽、生理盐水、生理盐水及东莨菪硷等实验组，除对照组外的各组动物在给药后50分钟注射东莨菪硷，10分钟后开始训练，将动物放入反应箱内适应环境3分钟，然后即通以36V的交流电。动物受到电击，其正常反应是跳回平台以躲避伤害性刺激，多数动物可能再次或多次跳至铜栅上，受到电击又迅速跳回平台上，反复训练5分钟记录第一次跳下平台的潜伏期和5分钟内的错误次数以此作为学习成绩。24小时后重新测验，以此作为记忆保持测验。实验证明从表1可见，记忆增强肽能明显改善东莨菪硷所致小白鼠学习记忆功能障碍。
与模型组比效0.5μg和1μg/Kg剂量，记忆增强肽明显改善东莨菪硷所致的学习记忆障碍，其潜伏期的延长和错误次数的减少均有显著性差异于(P＜0.01)与石杉硷甲(100μg/Kg)比较；记忆增强肽(0.5μg/Kg和1μg/Kg)对东莨菪硷所致学习障碍的改善作用比石杉硷甲好。
               表1记忆肽MEP-531对小白鼠学习记忆的影响
组别       给药剂量    东莨菪硷             学习成绩                      记忆成绩
           μg/Kg       mg/Kg      潜伏期(s)        错误次数      潜伏期(s)       错误次数
对照组     生理盐水      -        131.4±98.3       0.9±0.87     285.4+22.6      0.4±0.51
模型组     生理盐水      1        27.5±29.4▲▲    2.3±1.4▲    140±117▲▲    1.9±1.2▲▲
石杉硷甲    100          1        120.5±114.9*     1.3±2.3**    231.9±78**     0.9±0.7**
MEP-531     0.25         1        78.8±118.7       0.3±0.48**   197.6±75.1     0.9±0.56**
MEP-531     0.5          1        241.6±51.9**     0.2±0.4**    245.5±62.9**   0.5±0.5**
MEP-531     1            1        267.6±31.4**     0.3±0.5**    282.8±33.4**   0.3±0.5**
▲＜0.05，＜0.01，与对照组比较
*＜0.05，**＜0.01，与模型组比较
由此可看出，本发明的一类记忆增强肽可用于制备改善记忆障碍或促进儿童智力发育的药物或保健品。
(四)具体实施方式
实施例1
Asn·Cys(Bu′)·Pro·Arg(MEP422)的化学合成
2g Merrifield Resin开始采用Boc-系统逐步固相法合成。
首先从
Figure C0011687600062
(1)TFA/CH2Cl2(1∶1)30分钟
(2)Et3N/CH2Cl2
同上①，②步处理
上述粗产物经硅胶柱(Silicagel60)分离纯化，纯化过的产物再经C18HPLC分离纯化，HPLC层析中的出峰时间为19.1分钟，溶剂系统为TFA/乙腈系统。
                  氨基酸组成合理，分析结果如下：
实验值：    Asn：1.05      Arg：0.96       Pro：1.08    Cys：未测
理论：      Asn：1.00      Arg：1.00       Pro：1.00
质谱分析：分子离子峰544.3
X为Ala；Leu；Ile；Phe；Tyr；Val时，同样可采用上述方法制得相应产物。
实施例2 PyroGlu-Asn·Cys(S-But)·Pro·Arg(MEP531)的化学合成
2gMerrifield Resin开始采用Boc系统逐步固相法合成
首先从
Figure C0011687600075
同上①，②步处理
通过上述反应得五肽粗品，经硅胶柱层析分离纯化再经C18HPLC分离纯化，HPLC层析中的出峰时间为19.5分钟，溶剂系统为TEA/乙腈系统。氨基酸组成合理，分析结果如下：
实验值：  Asn：1.01    Glu：1.03    Arg：0.96    Pro：0.95     Cys：未测
理论：    Asn：1.00    Glu：1.00    Arg：1.00    Pro：1.00
质谱分析：分子离子峰687
X为Ala；Leu；Ile；Phe；Tyr：Val，时，同样可采用上述方法制得相应产物。

Claims (3)

1、一类记忆增强肽，其特征在于它的化学结构式为
Figure C0011687600021
X为Ala；Leu；He；Cys；Phe；Tyr；Val；
R1为PyroGlu；H；
R2为S-S-(CH3)3或S-(CH3)3。
2、根据权利要求1所述的一类记忆增强肽的制备方法，其特征在于该方法为固相多肽合成法或液相多肽合成法。
3、根据权利要求1所述的一类记忆增强肽在制备改善记忆障碍或促进儿童智力发育的药物或保健品中的应用。
CNB001168762A 2000-06-30 2000-06-30 一类记忆增强肽和它们的用途 Expired - Fee Related CN1154656C (zh)

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CNB001168762A CN1154656C (zh) 2000-06-30 2000-06-30 一类记忆增强肽和它们的用途
JP2002507844A JP4372417B2 (ja) 2000-06-30 2001-05-28 記憶強化ペプチド類及びその用途
EP01949207A EP1300416B1 (en) 2000-06-30 2001-05-28 Memory-enhancing peptides and the use thereof
US10/311,858 US7119063B2 (en) 2000-06-30 2001-05-28 Memory-enhancing peptides and the use thereof
PCT/CN2001/000875 WO2002002592A1 (en) 2000-06-30 2001-05-28 Memory-enhancing peptides and the use thereof
AU2001270451A AU2001270451A1 (en) 2000-06-30 2001-05-28 Memory-enhancing peptides and the use thereof

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CN109265514B (zh) * 2018-09-28 2021-03-30 华南理工大学 一种抗胃肠道消化的改善记忆肽及其用途

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IE56021B1 (en) * 1982-10-13 1991-03-27 Akzo Nv Peptides
IE58407B1 (en) * 1984-04-13 1993-09-22 Akzo Nv Peptides
KR0141693B1 (ko) * 1988-08-12 1998-06-15 나까무라 하루후미 펩티드 유도체 및 항치매제
DE69013742T2 (de) * 1989-04-15 1995-03-23 Nippon Chemiphar Co Peptide und diese Peptide enthaltende Wirkstoffe gegen Dementia.
CN1036010C (zh) * 1992-08-08 1997-10-01 中国科学院上海生物化学研究所 记忆增强肽及其应用

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EP1300416A4 (en) 2007-08-22
US7119063B2 (en) 2006-10-10
EP1300416B1 (en) 2012-07-11
JP4372417B2 (ja) 2009-11-25
CN1331083A (zh) 2002-01-16
EP1300416A1 (en) 2003-04-09

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