2. Academic Validation
  3. Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties

Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties

  • Nat Neurosci. 2022 Jan;25(1):39-49. doi: 10.1038/s41593-021-00971-w.
Zhangcheng Chen  # 1,  Luyu Fan  # 1,  Huan Wang  # 2,  Jing Yu  # 1,  Dengyu Lu  # 3,  Jianzhong Qi 1,  Fen Nie 1,  Zhipu Luo 4,  Zhen Liu 3,  Jianjun Cheng 5,  Sheng Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 2 iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 3 Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technolog, Chinese Academy of Sciences, Shanghai, China.
  • 4 Institute of Molecular Enzymology, Soochow University, Suzhou, China.
  • 5 iHuman Institute, ShanghaiTech University, Shanghai, China. [email protected].
  • 6 State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 34887590 DOI: 10.1038/s41593-021-00971-w
Abstract

Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs.

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