Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (11): 3916-3929.DOI: 10.6023/cjoc202303005 Previous Articles     Next Articles


沈冬杭a,b,c†, 李鑫a,b†, 郭世猛a,b, 谢欣a,b,c,*(), 南发俊a,b,c,*()   

  1. a 中国科学院大学 北京 100049
    b 中国科学院上海药物研究所 上海 201203
    c 杭州高等研究院 杭州 310024
  • 收稿日期:2023-03-02 修回日期:2023-05-25 发布日期:2023-07-05
  • 作者简介:

Design and Synthesis Studies of α-Methylene-γ-butyrolactones Antagonists of GPR52

Donghang Shena,b,c†, Xin Lia,b†, Shimeng Guoa,b, Xin Xiea,b,c(), Fajun Nana,b,c()   

  1. a University of Chinese Academy of Sciences, Beijing 100049
    b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
    c Hangzhou Institute for Advanced Study, Hangzhou 310024
  • Received:2023-03-02 Revised:2023-05-25 Published:2023-07-05
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  • About author:
    †These authors contributed equally to this work.

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 μmol/L). In this study, the structure of E7 was simplified and the α-methylene-γ-butyrolactone moiety was retained. And 34 novel α-methylene-γ-butyro- lactone derivatives were designed and synthesized, of which (±)-((2S,3R)-4-methylene-5-oxo-2-(thiophen-2-yl)-tetrahydro- furan-3-yl)methyl 4-methoxybenzoate (10m) showed most potent antagonistic activity against GPR52 (IC50=0.58 μmol/L). Meanwhile, the structure-activity relationship was determined preliminarily and the necessary of α-methylene-γ- butyrolactone moiety was verified.

Key words: Huntingdon’s disease, G protein-coupled receptor, GPR52, α-methylene-γ-butyrolactones, antagonist