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P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity

文献类型：期刊论文

作者Zhou, Pingzheng1; Zhang, Yangming2,3; Xu, Haiyan1; Chen, Fei2,3; Chen, Xueqin1; Li, Xiaoying2,3; Pi, Xiaoping1; Wang, Lipeng1; Zhan, Li1; Nan, Fajun2,3
刊名MOLECULAR PHARMACOLOGY
出版日期2015-01
卷号87期号:1页码:31-38
ISSN号0026-895X
DOI10.1124/mol.114.095190
文献子类Article
英文摘要Retigabine (RTG, [ethyl N-[2-amino-4-[(4-fluorophenyl)methyl] amino] phenyl] carbamate]) is a first-in-class antiepileptic drug that acts by potentiating neuronal KCNQ potassium channels; however, it has less than optimal brain distribution. In this study, we report that P-RTG (ethyl N-[2-amino-4-((4-fluorobenzyl) (prop-2-ynyl)amino)phenyl]carbamate), an RTG derivative that incorporates a propargyl group at the N position of the RTG linker, exhibits an inverted brain distribution compared with RTG. The brain-to-plasma concentration ratio of P-RTG increased to 2.30 compared with 0.16 for RTG. However, the structural modification did not change the drug's potentiation potency, subtype selectivity, or RTG molecular determinants on KCNQ channels. In addition, in cultured hippocampal neurons, P-RTG exhibited a similar capability as RTG for suppressing both induced and spontaneous action potential firing. Notably, P-RTG antiepileptic activity in the maximal electroshock (MES)-induced mouse seizure model was significantly enhanced to a value 2.5 times greater than that of RTG. Additionally, the neurotoxicity of P-RTG in the rotarod test was comparable with that of RTG. Collectively, our results indicate that the incorporation of a propargyl group significantly improves the RTG brain distribution, supporting P-RTG as a promising antiepileptic drug candidate. The strategy for improving brain-to-plasma distribution of RTG might be applicable for the drug development of other central nervous system diseases.
WOS关键词POTASSIUM CHANNEL OPENERS ; ANTICONVULSANT RETIGABINE ; K+ CHANNELS ; MOLECULAR DETERMINANTS ; SAFETY PROFILE ; ANIMAL-MODELS ; KCNQ2 OPENER ; DRUG DESIGN ; ACTIVATION ; EZOGABINE
资助项目National Science and Technology Major Project on Key New Drug Creation and Manufacturing Program[2013ZX09103001-016] ; State Key Program of Basic Research of China[2013CB910604] ; National Natural Science Foundation of China Grant for Excellent Key Laboratory[81123004] ; National Natural Science Foundation of China[61327014] ; National Natural Science Foundation of China[61175103] ; Shanghai Municipal Science and Technology Commission[13JC1406700] ; External Cooperation Program of BIC, Chinese Academy of Sciences[1536631KYSB20130003] ; SA-SIBS Scholarship Program[00000000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000346187500004
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
源URL[http://119.78.100.183/handle/2S10ELR8/276788]  
专题国家新药筛选中心
中科院受体结构与功能重点实验室
新药研究国家重点实验室
神经药理学研究国际科学家工作站
通讯作者Gao, Zhaobing
作者单位1.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening,State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Grad Sch, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Pingzheng,Zhang, Yangming,Xu, Haiyan,et al. P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity[J]. MOLECULAR PHARMACOLOGY,2015,87(1):31-38.
APA Zhou, Pingzheng.,Zhang, Yangming.,Xu, Haiyan.,Chen, Fei.,Chen, Xueqin.,...&Gao, Zhaobing.(2015).P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity.MOLECULAR PHARMACOLOGY,87(1),31-38.
MLA Zhou, Pingzheng,et al."P-Retigabine: An N-Propargyled Retigabine with Improved Brain Distribution and Enhanced Antiepileptic Activity".MOLECULAR PHARMACOLOGY 87.1(2015):31-38.

入库方式： OAI收割

来源：上海药物研究所

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