Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52
文献类型：期刊论文
| 作者 | Shen, Donghang1,2,3; Li, Xin1,2; Guo, Shimeng1,2; Xie, Xin1,2,3 ; Nan, Fajun1,2,3
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| 刊名 | CHINESE JOURNAL OF ORGANIC CHEMISTRY
 |
| 出版日期 | 2023-11-01 |
| 卷号 | 43期号:11页码:3916-3929 |
| 关键词 | Huntingdon's disease G protein-coupled receptor GPR52 alpha-methylene-gamma-butyrolactones antagonist |
| ISSN号 | 0253-2786 |
| DOI | 10.6023/cjoc202303005 |
| 通讯作者 | Xie, Xin(xxie@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn) |
| 英文摘要 | GPR52 is an orphan G protein-coupled receptor, which is highly expressed in the striatum and associated with Huntingdon's disease (HD), a neurodegenerative disease. HD is caused by the accumulation of mutant Huntingdon's protein (mHTT). Reduction of mHTT level by inhibition of GPR52 is a novel potential method of HD therapy. Through high throughput screening, the natural product E7 was found as a covalent antagonist against GPR52 (IC50=12.0 mu mol/L). In this study, the structure of E7 was simplified and the alpha-methylene-gamma-butyrolactone moiety was retained. And 34 novel alpha-methylene-gamma-butyro-lactone derivatives were designed and synthesized, of which (+/-)-((2S,3R)-4-methylene-5-oxo-2-(thiophen-2-yl)-tetrahydro-furan3-yl)methyl 4-methoxybenzoate (10m) showed most potent antagonistic activity against GPR52 (IC50=0.58 mu mol/L). Meanwhile, the structure-activity relationship was determined preliminarily and the necessary of alpha-methylene-gamma-butyrolactone moiety was verified. |
| WOS关键词 | HUNTINGTONS-DISEASE ; MUTANT HUNTINGTIN ; REVERSAL ; TARGETS ; SCREEN |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001135098600016 |
| 出版者 | SCIENCE PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308784]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Xie, Xin; Nan, Fajun |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shen, Donghang,Li, Xin,Guo, Shimeng,et al. Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52[J]. CHINESE JOURNAL OF ORGANIC CHEMISTRY,2023,43(11):3916-3929. |
| APA | Shen, Donghang,Li, Xin,Guo, Shimeng,Xie, Xin,&Nan, Fajun.(2023).Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52.CHINESE JOURNAL OF ORGANIC CHEMISTRY,43(11),3916-3929. |
| MLA | Shen, Donghang,et al."Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52".CHINESE JOURNAL OF ORGANIC CHEMISTRY 43.11(2023):3916-3929. |
入库方式： OAI收割
来源：上海药物研究所
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