2. Academic Validation
  3. Structure-Guided Design of Novel 5-HT2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects

Structure-Guided Design of Novel 5-HT2A Partial Agonists as Psychedelic Analogues with Antidepressant Effects

  • J Med Chem. 2025 Oct 23;68(20):21683-21700. doi: 10.1021/acs.jmedchem.5c02045.
Rongyan Li 1 2,  Haohan Yan 3,  Yujin Chen 1 2,  Yangyang Liu 1 2,  Lingjie Tang 3,  Jing Yu 3,  Junjun Liu 2,  Huan Wang 1,  Sheng Wang 3 4 5,  Jianjun Cheng 1 2
Affiliations

Affiliations

  • 1 iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 3 Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
  • 4 Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Xiangshan Zhinong, Hangzhou 310024, China.
  • 5 Shanghai Academy of Natural Sciences, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
PMID: 41087124 DOI: 10.1021/acs.jmedchem.5c02045
Abstract

Depression is primarily treated with selective serotonin reuptake inhibitors (SSRIs), which are limited by delayed onset of effects and low rates of remission. Recent studies showed that serotonergic psychedelics such as psilocybin can reduce depressive symptoms both rapidly and enduringly. Such effects have been associated with the activation of the serotonin 2A (5-HT2A) receptor in the central nervous system, which has prompted medicinal chemistry studies of novel 5-HT2A agonists. In this study, we designed and synthesized novel 5-HT2A partial agonists based on the structures of the antipsychotic drug aripiprazole and our previously reported lead compound IHCH-7086. Two series of new compounds were synthesized, a number of which exhibited potent 5-HT2A partial agonist activity in G protein coupling and β-arrestin2 recruitment assays. Compound 28c exhibited antidepressant effects in the mouse tail-suspension test without inducing head-twitch responses, supplementing the growing reservoir of nonhallucinogenic 5-HT2A agonists.

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