2. Academic Validation
  3. Design, synthesis and biological activities of piperidine-spirooxadiazole derivatives as α7 nicotinic receptor antagonists

Design, synthesis and biological activities of piperidine-spirooxadiazole derivatives as α7 nicotinic receptor antagonists

  • Eur J Med Chem. 2020 Dec 1;207:112774. doi: 10.1016/j.ejmech.2020.112774.
Han Zhang 1,  Xiaomeng He 2,  Xintong Wang 3,  Bo Yu 4,  Siqi Zhao 5,  Peili Jiao 6,  Hongwei Jin 7,  Zhenming Liu 8,  KeWei Wang 9,  Liangren Zhang 10,  Lihe Zhang 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: zhanghan930506@163.com.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: xhe@bjmu.edu.cn.
  • 3 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: wangxintong@bjmu.edu.cn.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: boyu@bjmu.edu.cn.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: 1811210124@bjmu.edu.cn.
  • 6 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: pelly@bjmu.edu.cn.
  • 7 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: jinhw@bjmu.edu.cn.
  • 8 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: zmliu@bjmu.edu.cn.
  • 9 Department of Pharmacology, Qingdao University School of Phamacy, Qingdao, 266021, PR China. Electronic address: wangkw@bjmu.edu.cn.
  • 10 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: liangren@bjmu.edu.cn.
  • 11 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: zdszlh@bjmu.edu.cn.
PMID: 32882607 DOI: 10.1016/j.ejmech.2020.112774
Abstract

α: 7 nicotinic acetylcholine receptors (nAChRs) expressed in the nervous and immune systems have been suggested to play important roles in the control of inflammation. However, the lack of antagonist tools specifically inhibiting α7 nAChR impedes the validation of the channel as therapeutic target. To discover a selective α7 antagonist, we started a pharmacophore-based virtual screening and identified a piperidine-spirooxadiazole derivative T761-0184 that acts as a α7 antagonist. A series of novel piperidine-spirooxadiazole derivatives were subsequently synthesized and evaluated using two-electrode voltage clamp (TEVC) assay in Xenopus oocytes. Lead compounds from two series inhibited α7 with their IC50 values ranging from 3.3 μM to 13.7 μM. Compound B10 exhibited α7 selectivity over other α4β2 and α3β4 nAChR subtypes. The analysis of structure-activity relationship (SAR) provides valuable insights for further development of selective α7 nAChR antagonists.

Keywords

Antagonists; Piperidine-spirooxadiazole derivatives; SAR; α7 nAChR.

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