AI-Driven Discovery and Optimization of Positive Allosteric Modulators for NMDA Receptors: Potential Applications in Depression.

Journal: Journal of medicinal chemistry
Published Date: Jul 31, 2025

Abstract

-Methyl-d-aspartate receptors (NMDARs) are extensively distributed throughout the central nervous system (CNS), and their dysfunction is implicated in depressive disorder. Positive allosteric modulators (PAMs) enhance the receptor's sensitivity and activity to agonists without direct activation. In this study, using structure-based virtual screening and artificial intelligence (AI)-assisted optimization, we identified , a benzene-substituted piperidinol derivative and potent GluN2A-selective PAM. showed higher efficacy ( = 397.7%) than GNE-3419 ( = 196.4%), reducing the EC values and increasing the values for glutamate/glycine at GluN2A receptor. In chronic restraint stress (CRS) mice, significantly alleviated depression-related behaviors in multiple behavioral assessments, highlighting its superior antidepressant effects. Preliminary studies also confirmed favorable pharmacokinetic (PK) profiles and blood-brain barrier (BBB) penetration for , with no signs of addiction, weight gain, or organ and tissue damage in mice. These results suggest that offers promising potential as a novel antidepressant with multiple antidepressant-like properties.

Authors

  • Tingting Yang
    School of Life Sciences, Nanjing University, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing 210000, China.
  • Tianrui Xiong
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Yixiao Wang
    Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou, Zhejiang, P.R. China.
  • Bin Xi
    Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, PR China.
  • Ruyun Liu
    School of Pharmacy, Ningxia Medical University, Shengli Street 1160, Yinchuan 750004, China.
  • Zihan Wang
    Graduate School, Beijing University of Chinese Medicine, Beijing, China.
  • Wenyu Zhu
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191 Beijing, P. R. China.
  • Dehua Lu
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Zhongwei Wang
    Department of Radiology, Baoshan People's Hospital, Baoshan, China.
  • Zhenming Liu
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191 Beijing, P. R. China.
  • Zhuo Huang
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Health Science Center, Peking University, Beijing, China.
  • Lin Ma
    Department of Radiation Oncology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, United States.
  • Juan Du
    Department of Hygiene Detection Center, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), Guangzhou, Guangdong, China.
  • Zhongtang Li
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • Liangren Zhang
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191 Beijing, P. R. China.

Keywords

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