中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 国家新药筛选中心
Discovery of a Negative Allosteric Modulator of GABA(B) Receptors

文献类型：期刊论文

作者Chen, Lin-Hai1; Sun, Bing2; Zhang, Yang2; Xu, Tong-Jie2; Xia, Zhi-Xiong2; Liu, Jian-Feng2; Nan, Fa-Jun1
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2014-07
卷号5期号:7页码:742-747
关键词GABA(B) receptors negative allosteric modulator CGP7930 alpha-keto acid
ISSN号1948-5875
DOI10.1021/ml500162z
文献子类Article
英文摘要Initialized from the scaffold of CGP7930, an allosteric agonist of GABA(B) receptors, a series of non-competitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABA(B) receptors and Gq(j9) proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA(B) receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA(B) receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 mu M and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluRS. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABA(B) receptors, demonstrating that compound 14 negatively modulated GABA(B) receptors activity as a negative allosteric modulator.
WOS关键词ACTIVITY-BASED PROBE ; BACLOFEN ; GAMMA ; TRANSACTIVATION ; COMPLEXES ; SUBUNITS ; GS39783 ; LIGANDS ; NEURONS ; BINDING
资助项目Ministry of Science and Technology[2012CB518000] ; National Natural Science Foundation of China (NSFC)[31130028] ; National Natural Science Foundation of China (NSFC)[31225011] ; National Natural Science Foundation of China (NSFC)[91213303] ; Program of Introducing Talents of Discipline to the Universities of the Ministry of Education[B08029] ; Merieux Research Grants Program of Institut-Merieux[00000000]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000338981100007
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/276998]  
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
通讯作者Liu, Jian-Feng
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China;
2.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Minist Educ, Cellular Signaling Lab,Key Lab Mol Biophys, Wuhan 430074, Hubei, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Lin-Hai,Sun, Bing,Zhang, Yang,et al. Discovery of a Negative Allosteric Modulator of GABA(B) Receptors[J]. ACS MEDICINAL CHEMISTRY LETTERS,2014,5(7):742-747.
APA Chen, Lin-Hai.,Sun, Bing.,Zhang, Yang.,Xu, Tong-Jie.,Xia, Zhi-Xiong.,...&Nan, Fa-Jun.(2014).Discovery of a Negative Allosteric Modulator of GABA(B) Receptors.ACS MEDICINAL CHEMISTRY LETTERS,5(7),742-747.
MLA Chen, Lin-Hai,et al."Discovery of a Negative Allosteric Modulator of GABA(B) Receptors".ACS MEDICINAL CHEMISTRY LETTERS 5.7(2014):742-747.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。