靶向电压门控KCNQ/M钾通道的调节剂对神经精神疾病的潜在治疗作用

doi:10.5246/jcps.2014.01.001

中国药学(英文版) ›› 2014, Vol. 23 ›› Issue (1): 5-15.DOI: 10.5246/jcps.2014.01.001

靶向电压门控KCNQ/M钾通道的调节剂对神经精神疾病的潜在治疗作用

卞希玲, 王克威^*

1. 北京大学药学院分子与细胞药理学系; 天然药物及仿生药物国家重点实验室, 北京 100191
2. 北京大学 IDG麦戈文脑研究所, 北京 100871

收稿日期:2013-06-05 修回日期:2013-08-19 出版日期:2014-01-23 发布日期:2014-01-22
通讯作者: 王克威*
作者简介:*Corresponding author. Tel./Fax: 86-10-82805065; E-mail: wangkw@hsc.pku.edu.cn
基金资助:
National Natural Science Foundation of China (Grant No. 81000552, 30970919 and 81221002) and the Ministry of Science and Technology of China (Grant No. 2013CB531300).

Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders

Xiling Bian, Kewei Wang^*

1. Department of Molecular and Cellular Pharmacology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
2. PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China

Received:2013-06-05 Revised:2013-08-19 Online:2014-01-23 Published:2014-01-22
Contact: Kewei Wang*
About author:*Corresponding author. Tel./Fax: 86-10-82805065; E-mail: wangkw@hsc.pku.edu.cn
Supported by:
National Natural Science Foundation of China (Grant No. 81000552, 30970919 and 81221002) and the Ministry of Science and Technology of China (Grant No. 2013CB531300).

摘要/Abstract

摘要：

1980年David Brown博士首次发现了M型乙酰胆碱受体激动剂可以抑制一种钾通道电流, 并将其命名为M型钾电流(I_M); 十八年后科学家们克隆了导致新生儿癫痫的KCNQ2和KCNQ3突变基因, 并且证明KCNQ2和KCNQ3亚基异源组装介导M型钾通道电流。电压门控KCNQ2/3钾通道(亦称M通道)功能降低可导致神经元的过度兴奋, 诱发癫痫及慢性疼痛。因此, 研发激活KCNQ2/3通道功能的开放剂可用于治疗癫痫和疼痛等神经疾病。著名的KCNQ通道开放剂瑞替加滨retigabine(商品名Potiga)于2011年被美国食品与药品监督管理局批准治疗癫痫。我们最近参与研发了一类新型的KCNQ2/3特异性开放剂—吡唑并[1,5-a]嘧啶酮类化合物。在动物模型上, 该开放剂具有抗癫痫和镇痛的效果。最近的研究工作提示, KCNQ通道开放剂还对抑郁症、焦虑症和精神分裂症等动物模型有效, 而KCNQ通道抑制剂可以提高动物的学习与记忆能力。目前的研究进展提示, 电压门控KCNQ/M通道是治疗神经精神类疾病的靶点, 靶向该通道的调节剂对多种神经精神疾病具有潜在的治疗价值。

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王克威博士, 现任北京大学药学院分子与细胞药理学系教授、主任, 兼神经生物学教授, 北京大学麦戈文脑研究所首席研究员, 教育部长江学者、创新团队带头人。1988年毕业于北京大学医学部并获神经生理学博士学位。1988年至1993年在剑桥大学作为博士后从事离子通道的生物物理学和药理学研究。1993年至1997年, 在耶鲁大学生理系作为博士后及研究员, 从事离子通道的结构与生物物理功能方面的研究。1997年至2006年间, 在美国惠氏(Wyeth)制药公司神经科学研发部先后任高级和首席研究员并担任课题团队首席, 从事新药靶点鉴别、优化、先导化合物筛选以及治疗癫痫、疼痛和神经精神等疾病的创新药物研发。
王克威实验室长期以来从事离子通道的神经生物学功能与创新药物研发的应用研究, 获得了国家自然科学重点项目、面上项目基金、科技部863、973、重大新药创制基金以及教育部985基金的支持。在Neuron、Nature Neurosci、Nature和PNAS等杂志发表论文60余篇、专著章节3部, 获专利7份。

卞希玲博士, 北京大学药学院分子与细胞药理学系讲师, 研究方向为天然药物的离子通道靶点的鉴定及离子通道的神经生物学功能。2002年至2008年期间在中国科学院上海神经科学研究所, 北京生命科学研究所, 中国科学院生物物理研究所进行硕博连读学习, 师从李朝义院士和罗敏敏研究员。2008年获得中国科学院生物物理研究所博士学位后, 进入北京大学医学部, 在王克威实验室从事研究工作。先后承担基金三项, “国家自然基金(青年基金)”, “北京市青年英才计划”, 北京大学医学部新教师启动基金。以第一作者/共同第一作者的身份在《自然-通讯》等杂志发表SCI研究论文4篇。曾被评选为北京大学医学部优秀教师。

关键词: Kv7.2通道, 瑞替加滨, XE991, 癫痫, 疼痛

Abstract:

M-type potassium current (I_M) was initially isolated from sympathetic neurons in 1980 and named as it was inhibited by muscarine. In 1998, the molecular identity of M-current was revealed to be heterotetramers of KCNQ2 and KCNQ3 subunits, whose mutations cause neonatal epilepsy. Reduction of voltage-gated KCNQ2/3 K⁺ channel (M-channel) activity leads to neuronal hyperexcitability that defines the fundamental mechanism of neurological disorders such as epilepsy and pain. Thus, suppression of neuronal hyperexcitability by activation of KCNQ2/3 channels serves the basis for development of the channel openers for treatment of epilepsy and pain. The well-known KCNQ opener is retigabine (Potiga) that was approved by FDA as an antiepileptic drug in 2011. Recent studies also provide evidence that KCNQ2/3 channel openers are effective in animal models of bipolar disorder, anxiety and schizophrenia, whereas KCNQ2/3 inhibitors, on the other hand, are indicated for improvement of learning and memory in animal models. We recently designed and validated a novel series of pyrazolo [1,5-a]pyrimidin-7(4H)-ones (PPOs) that selectively activate KCNQ2/3 and show antiepileptic and analgesic activity in vivo. Up to date, all the progress made enforces the view that targeting voltage-gated KCNQ/M-channel may provide therapeutic potential for treatment of neuropsychiatric disorders.

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Dr. KeWei Wang is currently an endowed ChangJiangProfessor and Chair of the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where his overall research in the lab is directed towards understanding structure and molecular mechanisms of ion channels, and to identify and validate ion channel targets that are helpful for proving therapeutic potential of channel modulators for treatment of neuropsychiatric disorders.Currently, two classes of ion channels, voltage-gated potassium (Kv) and ligand-gated TRP channels,are investigated for their role in modulation of neurological function and pathology in the brain using cutting-edge technologies such as patch clamping electrophysiology and confocal Ca²⁺/FRET imaging with combination of molecular biology and in vivo pharmacology.
Dr. Wang graduated with M.D. in medicine and obtained his Ph.D. in neurophysiology from Peking University Medical School in 1988. From 1988 to 1997, he went to the University of Cambridge and then Yale University for postgraduate studies/training in disciplines of pharmacology, biophysics and physiology. From 1997 to 2006, he as a principal scientist/team leader worked on ion channel target related drug discovery/research for pain and pain-related neurological disorders at Wyeth Neuroscience, Princeton, New Jersey. He published over 60 peer-reviewed articles in journals such as Neuron, Nature Neurosci, PNAS, Nature, JBC, and Biophysiol J. etc, and was granted for 7 patents. Since 2008, he serves a review editor for several journals including “Front. Neurosci” and “Pharm. Sin. B”, etc..

Dr. Xiling Bian is currently a Lecturer in the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where she is trying to identify the ion channel-targets of natural medicine and explore neurological functions of ion channels. Dr. Bian received her Ph.D. in neuroscience from Chinese Academy of Sciences in 2008 with her research topic ‘Pheromone-Processing Circuits in the Medial Amygdala’. After that, Dr. Bian entered Peking University Health Science Center. She has published four first (co-first) authored research articles in scientific journals such as Nature Communications. She received three grants, including one grant from National Natural Science Foundation of China and another one from Beijing City Youth Talent Plan. She was honored as Model Teacher of Peking University Health Science Center in 2011.

Key words: Kv7.2, Retigabine, XE991, Epilepsy, Pain

中图分类号:

R971

Supporting: *Corresponding author. Tel./Fax: 86-10-82805065; E-mail: wangkw@hsc.pku.edu.cn

卞希玲, 王克威*. 靶向电压门控KCNQ/M钾通道的调节剂对神经精神疾病的潜在治疗作用[J]. 中国药学(英文版), 2014, 23(1): 5-15.

Xiling Bian, Kewei Wang*. Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(1): 5-15.

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靶向电压门控KCNQ/M钾通道的调节剂对神经精神疾病的潜在治疗作用

Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders

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