<strong>一种新型的抗老年痴呆剂:左旋黄皮酰胺的化学、生物学活性和作用机制研究</strong>

神经药理学报››2014,Vol. 4››Issue (6): 33-43.

一种新型的抗老年痴呆剂:左旋黄皮酰胺的化学、生物学活性和作用机制研究

楚世峰，张均田

中国医学科学院药物研究所

出版日期:2014-12-26发布日期:2015-01-20
通讯作者:张均田，男，博士生导师；研究方向：神经药理学；E-mail:zhangjt@imm.ac.cn
作者简介:楚世峰，男；研究方向：神经药理学
基金资助:

本项目得到科技部973计划的资助，已取得中国、美国和欧盟专利证书，获教育部自然科学奖一等奖，中华医学奖二等奖，北京市科技进步奖二等奖各一项，在SCI杂志上发表的论文五十余篇。

A New Type of Anti-dementia Drug: The Chemistry, Biological Activities and Mechanism of Action of (-) Clausenamide

CHU Shi-feng, ZHANG Jun-tian

Institute of material medica, Chinese academy of medical sciences, China

Online:2014-12-26Published:2015-01-20
Contact:张均田，男，博士生导师；研究方向：神经药理学；E-mail:zhangjt@imm.ac.cn
About author:楚世峰，男；研究方向：神经药理学
Supported by:

本项目得到科技部973计划的资助，已取得中国、美国和欧盟专利证书，获教育部自然科学奖一等奖，中华医学奖二等奖，北京市科技进步奖二等奖各一项，在SCI杂志上发表的论文五十余篇。

摘要/Abstract

摘要：从芸香科植物黄皮叶中分离出具有五种不同骨架的七个新酰胺类化合物，其中之一的黄皮酰胺的γ-内酰胺与具有促智作用的脑复康（piracetam）呈现相同的骨架，它的分子中有4个不对称中心，应有16个对映体。在鉴定出16个对映体的绝对构型之后，用黄量教授设计的仿生路线先后完成了16个对映体和光活黄皮酰胺的不对称合成，在这一研究中解决了立体化学和合成中的一些难点，大大缩短了合成步骤，提高了总得率，生产工艺日趋成熟，其合成规模可满足临床试用和日后治疗疾病的需要。使用多项模型和指标业已证明（-）黄皮酰胺是有效对映体，（+）黄皮酰胺为劣对映体。黄皮酰胺对映体的代谢（血药浓度、吸收、分布、排泄、血浆蛋白结合、肝脏首过效应）和酶促动力学也都存在立体选择性差异。（-）黄皮酰胺的主要药理作用是改善认知功能和抑制Aβ毒性，促智，抗凋亡和抑制Tau蛋白过度磷酸化的机制均已阐明。药理作用的显著特点是提高突触效能和结构的可塑性，为国际上近年提出的“突触丢失是老年痴呆的主要原因”的新学说提供了有力的支持，也为当前AD治疗的新策略提供了有良好前景的新药。

关键词:左旋黄皮酰胺,对映体,认知,阿尔茨海默病,突触可塑性

Abstract:Seven novel amides were isolated from clausena lansium (Lour) skeels, one of which is clausenamide. Clausenamide contains 4 chiral centers, which correspond to 16 enantiomers. After the identification of the configuration of 16 enantiomers, all were successfully synthesized, and the asymmetric synthesis of (+) and (-) clausenamide were completed. During this process, the production scale has been substantially increased that should be adequate to meet the clinical use. Pharmacological studies have shown that (-) clausenamide is the effective enantiomer, while (+) clausenamide is ineffective and more toxic than (-)clausenamide using different animal models. (-)clausenamide can increase cognitive function and inhibit Aβ pathology. The anti-dementia mechanism is characterized as increasing synaptic function and structural plasticity. . Together, (-)clausenamide may be a promising pharmacotherapy for the treatment of AD and other neurodegenerative disorders.

Key words:(-) clausenamide,enantiomers,cognition,Alzheimer&,rsquo,s disease (AD),synaptic plasticity

中图分类号:

R965

楚世峰，张均田.一种新型的抗老年痴呆剂:左旋黄皮酰胺的化学、生物学活性和作用机制研究[J]. 神经药理学报, 2014, 4(6): 33-43.

CHU Shi-feng, ZHANG Jun-tian.A New Type of Anti-dementia Drug: The Chemistry, Biological Activities and Mechanism of Action of (-) Clausenamide[J]. Acta Neuropharmacologica, 2014, 4(6): 33-43.

参考文献

[1]黄量，张均田，吴克美，等光活（-）黄皮酰胺制备方法。中国发明专利。专利号：2100124630.5.

[2]Dan Fei Huang, Han Sen Lin, Liang Huang. Total systhesis of neoclausenamide and its epimer[J]. Chinese Chemical Letter, 1994, 5(5):371-372.

[3]Guo Bin Huang, Ke Mei Wu, Liang Huang, et al. Intracelluar induction of asymmetric Danzen’s condensation of aldehydes with chiral chloroaletates[J]. Chinese Chemical Letter, 1999, 10(6):441-442.

[4]黄国宾，吴克美，黄量. (+)-1S,2R,5S-8-β-萘基薄荷醇的合成[J].高等学校化学学报, 1990, 20（9）：1394-1399.

[5]Jun-tian Zhang, Liang Huang, Kemei Wu et al. Optically active clausenamides possess of the preparation thereof, pharmaceutical composition containing the same and their medical use[J]. Patent No. US:6787,564, B2. Date of Patent: Sep 7, 2004.

[6]Xing Zhou Li, Ke Mei Wu, Liang Huang. Study on the synthesis of metabolite of clausenamide(CM1)[J]. Chinese Chemical Letter, 2002, 13(6):528-530.

[7]Xin Zhou, Ke Mei Wu, Liang Huang. Study on the synthesis od metabolite CM2 of clausenamide[J]. Chemical Letter, 2003, 14(4):338-340.

[8]黄量, 王慕邹, 张均田, 手性黄皮酰胺的化学与生物学[M]//黄量, 戴立信, 手性药物的化学与生物学.北: 化学工业出版社, 2002: 6-16.

[9]Shao Lin Liu, Jun Tian Zhang. Effects of naloxone on L-clausenamide induced long term potentiation in dentate gyrus of anaesthetized rats[J]. Acta Pharmacol Sin, 1999, 20(2):112-116.

[10]Lin Xu, Shao Lin Liu, Juntian Zhang. (-)clausenamide potentiate synaptic transmission in the dentate gyrus of rats[J].Chirality, 2005, 17(5):239-244.

[11]Kang Tang, Jun Tian Zhang. Mechanism of (-)clausenamide induced calcium transient in primary culture of rat cortical neurons[J]. Life Science, 2004, 74:1427-1434.

[12]Wen Zhen Duan, Jun Tian Zhang. Stimulation of central cholinergic neurons by (-)clausenamide in vitro[J]. Acta Pharmacol Sin, 1998, 19(4):332-336.

[13]Wen Zhen Duan, Jun Tian Zhang. Effect of clausenamide on anisodine induced acrtycholine decrease and memory deficit in the mouse brain[J]. Chinese Medical Journal, 1998, 111(11):1035-1038.

[14]Xue Ying Jiang, Jun Tian Zhang. Study on the noontropic mechanism of (-)clausenamide on the formation of synapses in mouse brain[J]. J Asian Natural Products Res, 1998, 1:53-58.

[15]Dennis J Selkoe. Alzheimer’s disease is synaptic failure[J]. Science. 2000,298(5594):789-791.

[16]Na Ning, Jin Feng Hu, Jian Dong Sun et al. (-)clausenamide facilitates synaptic transmission at hippocampal schaffer collateral-CA1 synapses[J]. European J Pharmacology, 2012, 682:50-55.

[18]Jin Feng Hu, Na Ning, Wen Zhen Duan, et al. Activation of ERK1/2-CREB pathway during potentiating synaptic transmission of (-)clausenamide in rat dentate gyrus[J]. J Asian Natural Products Research, 2012, 14(3):256-262.

[19]王润生,张均田. Baxα高表达PC12细胞系的建立及（-）黄皮酰胺抗细胞凋亡作用机制的研究[J].药学学报，2000, 35（6）：404-407.

[20]张均田,王润生, 段文贞. 光活黄皮酰胺的抗神经细胞凋亡作用及作用机制的研究[m].//中国医学科学院中国协和医科大学科研处编.科学年会论文集.北京：中国协和医科大学出版社，2000:187-192.

[21]张静, 程勇, 张均田. 左旋黄皮酰胺对冈田酸和β淀粉样肽25-35神经毒性的保护作用[J]. 药学学报, 2007,42(9): 935-942.

[22]张均田.黄皮叶中具有促智作用的黄皮酰胺类化合物的化学和生物学研究[M]//中草药现代研究.北京.中国协和医科大学出版社, 2010:355-360.

[23]Hutt A J, Tan S C. Drugs chirality and its significance[J]. Drug, 1966, 52(suppl 5):1-12.

[24]Crossley R. The relevance of chirality to the study of biological activity[J]. Tetrahedron, 1992, 48(38):8155-8178.

[25]Tokuma Y, Neguchi H. stereoselective pharmacokinetics of dihydropyridine calcium antagonists[J]. J chrom A, 1995, 694:181-193.

[26]Caldwell J. Importance of stereospecific bioanalytical monitoring in drug development[J]. J chrom A, 1996, 719: 3-13.

[27]Williams K M Chirality: pharmacokinetics and pharmacodynamics in 3 dimensions[J]. Chiral and Exper Pharmacol Physio, 1989, 16:465-470.

[28]戴立信. 绪论[M]//见黄量戴立信,手性药物的化学与生物学.北京化学工业出版社 2002:1-6.

[29] A J Bayer, R Bullock, R W Jones, et al. Evaluation of the safety and immunogenicity of synthetic Aβ42 in patient with AD[J].Neurology, 2005, 64(1):94-101.

[30]徐庆中，卢德宏，董彬，等．Alzheimer’型老年痴呆的神经病理学[M]// 盛树力．老年性痴呆从分子生物学到临床诊治.北京：科学文献出版社，1998:78-79

[31] Dennis J Selkoe．Alzheimer’s disease in a synaptic failure[J]. Science, 2000, 298(5594)：789-791.

[32] Robert D．Terry Some morphometric aspects of the brain in senile dementia of the Alzheimer type[J]. Ann Neuro1, 1981, 10(2): 184-l92.

[33]Veronica A Alvanez, Bernando L Sabatini. Anatomical and physiological plasticity of dendritic spines[J]. Annu Rev Neurosci, 2007, 30:79-97.

[34]Claudia Ferez-Cruz. Reduced spine density in specific regions of CA 1 pyramidal neurons in two transgenic mouse models of Alzheimer’s disease [J].J Neurosci, 2011, 31(10)：3926-3934.

[35] Ryan Clare, Victoria G King, Martin Wirenfeldt, et a1.Vinters．Synapse loss in dementias[J].J Neurosci Res, 2010, 88 (101):2083-2090.

[36]Veronica A Alvarez, Bernardo L Sabatini, Annu Rev. Anatomieal and physiological plasticity of dendritic spines[J]. Annu Rev Neurosci, 2007, 30:79-97.

[37]Giles E, Hardinham, Hilmar Bading. Synaptic versus extra-synaptic NMDA receptor signaling：implications for neuro-degenerative disorders[J].Nat Rev Neurosci, 2010, 10:682-696.

[38]张均田，郑永芳．细胞内钙和钙通道[M]//韩济生．神经科学原理．上册2版，北京：北京医科大学出版社，1999：222-240.

[39]Kelly AFoster, Nathan McLaughlin, Dieter Edbauer, et a1．Distinct roles of NR2A and NR2B cytoplasmic tails in long term potentiation [J]. J Neurosci, 20l0, 30(7)：2676-2685

[40] Boeckers TM. The postsynaptic density[J]. Cell Tissue Res, 2006, 326(2)：409-422.

[41]Gong Yuesong, Card F Lippa. Disruption of the postsynaptic density in Alzheimer’s disease and other neurOdegenerative dementias[J]. Am J Alzheimers Dis Other Demen, 2010, 25(71)：547-555.

一种新型的抗老年痴呆剂:左旋黄皮酰胺的化学、生物学活性和作用机制研究

A New Type of Anti-dementia Drug: The Chemistry, Biological Activities and Mechanism of Action of (-) Clausenamide

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章15

编辑推荐

Metrics

[1]	谢彬, 黄志源, 林多朵, 杨福龙, 谢奕彬.针药结合干预阿尔茨海默病抑郁症状效果分析[J]. 神经药理学报, 2020, 10(5): 5-8.
[2]	赵雨薇, 甄艳杰, 戴月英, 沈丽霞.槲皮素对阿尔茨海默症神经保护作用研究[J]. 神经药理学报, 2020, 10(5): 55-64.
[3]	海吉涛, 罗焕敏.病原微生物与阿尔茨海默病相关性研究进展[J]. 神经药理学报, 2020, 10(4): 58-64.
[4]	杨旭华, 杜爽, 沈丽霞, 郝军荣.阿尔茨海默病的药物治疗研究进展[J]. 神经药理学报, 2020, 10(3): 47-53.
[5]	孙逸, 侯雪芹, 王福刚.当归芍药散改善认知功能的研究进展[J]. 神经药理学报, 2020, 10(3): 42-46.
[6]	刘璇, 滕金亮.右美托咪定对术后认知功能障碍影响的研究进展[J]. 神经药理学报, 2020, 10(2): 39-45.
[7]	甄艳杰, 郭童林, 赵雨薇, 沈丽霞.植物雌激素介导线粒体途径对阿尔茨海默病神经保护作用的研究进展[J]. 神经药理学报, 2020, 10(1): 40-46.
[8]	杨琳，艾静.脑源雌激素在阿尔茨海默病中的作用研究进展[J]. 神经药理学报, 2019, 9(5): 50-64.
[9]	张帅，艾静.谷氨酸功能异常与阿尔茨海默病[J]. 神经药理学报, 2018, 8(6): 9-20.
[10]	SHEN li-xia1，LIU Liang-liang1，ZHANG Ming1，LIU Yang1，ZHANG Dan-shen 2*.Research of Quercetin’s Estrogen-Like Action on Central Nervous System and Its Mechanisms[J]. 神经药理学报, 2018, 8(4): 23-25.
[11]	朱敏1,李凌海2.麻醉药物应用与患者术后认知功能障碍的研究进展[J]. 神经药理学报, 2018, 8(3): 32-.
[12]	黄蕊，杨翠翠，张兰.二苯乙烯苷对APP/PS1 双转基因小鼠学习记忆及突触可塑性的影响[J]. 神经药理学报, 2018, 8(2): 31-31.
[13]	曾菊，程斌，程肖蕊，周文霞，张永祥.基于LPS 诱导小鼠炎症模型的LW-AFC 抗炎作用研究[J]. 神经药理学报, 2018, 8(2): 49-49.
[14]	雷曦，王健辉，程肖蕊，张小锐，刘港，周文霞，张永祥.基于快速老化模型小鼠SAMP8 的CA-30 抗阿尔茨海默病的作用研究[J]. 神经药理学报, 2018, 8(2): 50-50.
[15]	王健辉，程肖蕊，张小锐，刘港，周文霞，张永祥.药物组合吲哚美辛与阿托伐他汀对阿尔茨海默病的治疗作用研究[J]. 神经药理学报, 2018, 8(2): 52-52.