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2023 , Vol. 43 >Issue 11: 3916 - 3929

DOI: https://doi.org/10.6023/cjoc202303005

研究论文

α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究

  • 沈冬杭 ,
  • 李鑫 ,
  • 郭世猛 ,
  • 谢欣 ,
  • 南发俊
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  • 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
†共同第一作者

收稿日期: 2023-03-02

  修回日期: 2023-05-25

  网络出版日期: 2023-07-06

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

  • Donghang Shen ,
  • Xin Li ,
  • Shimeng Guo ,
  • Xin Xie ,
  • Fajun Nan
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  • 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
†These authors contributed equally to this work.
* E-mail: ;

Received date: 2023-03-02

  Revised date: 2023-05-25

  Online published: 2023-07-06

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摘要

GPR52是一种孤儿G蛋白偶联受体, 在纹状体中高度表达, 与神经退行性疾病亨廷顿舞蹈症(HD)的发生相关. 变异亨廷顿蛋白(mHTT)的蓄积是亨廷顿舞蹈症的主要发病原因. 通过拮抗GPR52活性降低mHTT的水平是一种有潜力的新型治疗手段. 通过高通量筛选, 发现天然产物E7作为共价拮抗剂对GPR52具有一定的抑制作用(IC50=12.0 μmol/L). 本工作通过保留关键母核α-亚甲基-γ-丁内酯, 对E7进行结构简化并改造, 设计合成了34个新型α-亚甲基-γ-丁内酯衍生物, 其中(±)-4-甲氧基苯甲酸-[(2S,3R)-4-甲亚基-5-氧亚基-2-(噻吩-2-基)四氢呋喃-3-基]甲基酯(10m)对GPR52具有较好的拮抗活性(IC50=0.58 μmol/L). 同时, 初步确定了此类新型GPR52拮抗剂的构效关系, 并验证了α-亚甲基-γ-丁内酯母核的必要性.

关键词： 亨廷顿舞蹈症; G蛋白偶联受体; GPR52; α-亚甲基-γ-丁内酯; 拮抗剂

本文引用格式

沈冬杭 , 李鑫 , 郭世猛 , 谢欣 , 南发俊 . α-亚甲基-γ-丁内酯类GPR52拮抗剂的设计与合成研究[J]. 有机化学, 2023 , 43(11) : 3916 -3929 . DOI: 10.6023/cjoc202303005

Abstract

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

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