2. Academic Validation
  3. Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical antipsychotics

Synthesis and biological investigation of triazolopyridinone derivatives as potential multireceptor atypical antipsychotics

  • Bioorg Med Chem Lett. 2020 Apr 15;30(8):127027. doi: 10.1016/j.bmcl.2020.127027.
Wenqiang Shi 1,  Yu Wang 2,  Chunhui Wu 3,  Feipu Yang 2,  Wei Zheng 1,  Song Wu 3,  Yongjian Liu 3,  Zhen Wang 4,  Yang He 5,  Jingshan Shen 1
Affiliations

Affiliations

  • 1 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 2 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 3 Topharman Shanghai Co., Ltd, 388 Jialilue Road, Shanghai 201203, China.
  • 4 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: wangzhen@simm.ac.cn.
  • 5 CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: heyang@simm.ac.cn.
PMID: 32122737 DOI: 10.1016/j.bmcl.2020.127027
Abstract

A series of triazolopyridinone derivatives originating from the antidepressant trazodone was designed and pharmacologically evaluated. Most of the compounds with a multireceptor functional profile exhibited high potency at the D2, 5-HT1A, and 5-HT2A receptors. Compounds S1, S3, S9 and S12 were selected for further evaluation of druggable potential. Among these compounds, S1, as a D2 receptor partial agonist, demonstrated very potent inhibition of quipazine-induced head-twitch response, which validated its 5-HT2A receptor antagonistic efficacy in vivo. S1 also demonstrated a dose-dependent effect on PCP-induced hyperactivity when administered orally. Thus, S1 endowed with a triazolopyridinone scaffold represents a valuable lead for the development of novel atypical antipsychotics.

Keywords

5-HT1A receptor; Antipsychotic; Multireceptor; Triazolopyridinone.

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