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中国药学(英文版) ›› 2017, Vol. 26 ›› Issue (7): 504-511.DOI: 10.5246/jcps.2017.07.056

• 【研究论文】 • 上一篇    下一篇

异黄酮类CLR/RAMP1拮抗剂的设计、合成及生物活性评价

王俊杰, 王超, 吕鹏, 牛彦*, 李宏月, 黄文慧, 李灿, 许凤荣, 梁磊, 徐萍*   

  1. 北京大学医学部 药学院 药物化学系, 北京 100191
  • 收稿日期:2017-04-29 修回日期:2017-05-20 出版日期:2017-07-28 发布日期:2017-06-19
  • 通讯作者: Tel.: +86-010-82805281, E-mail: yanniu@bjmu.edu.cn
  • 基金资助:

    National Basic Research Program of China (Grant No. 2012CB518000), Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120001110010).

Design, synthesis and bioevaluation of isoflavone derivative as a novel CLR/RAMP1 antagonist

Junjie Wang, Chao Wang, Peng Lü, Yan Niu*, Hongyue Li, Wenhui Huang, Can Li, Fengrong Xu, Lei Liang, Ping Xu*   

  1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
  • Received:2017-04-29 Revised:2017-05-20 Online:2017-07-28 Published:2017-06-19
  • Contact: Tel.: +86-010-82805281, E-mail: yanniu@bjmu.edu.cn
  • Supported by:

    National Basic Research Program of China (Grant No. 2012CB518000), Specialized Research Fund for the Doctoral Program of Higher Education of China (Grant No. 20120001110010).

摘要:

本文通过分析已有CLR/RAMP1胞外区与其拮抗剂分子共结晶结构以及已有小分子拮抗剂Telcagepant的构效关系, 借助计算机辅助药物设计方法, Telcagepant为模板进行形状筛选以得到结构新颖化合物, 结合对接优化设计得到具有异黄酮结构母核的全新结构的化合物作为CLR/RAMP1拮抗剂。完成了化合物合成及细胞水平活性评价, 为之后继续进行结构优化改造奠定基础。

关键词: 异黄酮, CLR/RAMP1拮抗剂, 研究

Abstract:

CGRP receptor (CLR) is a B class GPCR that functions only when combined with RAMPs. CLR/RAMP1 has been regarded as a promising target for migraine treatment, as its antagonists have been proved to be effective recently. In the present study we designed and synthesized small molecular antagonists against CLR/RAMP1, resulting in a novel type of structure with acceptable high potency. The molecules were designed via virtual screening. Afterwards, a series of modification were conducted on the hit compounds, resulting in compound 8 as the best scored compound in docking, which was further validated in vitro by cell-based functional assay. 

Key words: Isoflavone, CLR/RAMP1 antagonist, Research

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