Identification of a Potent and Selective Small-Molecule Inhibitor Targeting the nNOS-PDZ Domain that Exhibits Rapid In Vivo Antidepressant Efficacy

  • J Med Chem. 2026 Jun 25;69(12):14513-14529. doi: 10.1021/acs.jmedchem.6c00391.
Liting Zhang  1  2 ,  Zijie Xiong  1  2 ,  Shasha Chen  1  2 ,  Qiucheng Zhu  1  2 ,  Yifei Wang  1  2 ,  Qi Lu  3 ,  Xiaohan Bu  1  2 ,  Anjie Xia  4 ,  Lijuan Chen  5 ,  Chong Chen  1 ,  Zhenhua Shao  6 ,  Linli Li  3 ,  Shengyong Yang  1  2
Affiliations
  • 1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan610041, China.
  • 2. New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan610041, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan610041, China.
  • 4. Department of Ophthalmology and Laboratory of Macular Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan610041, China.
  • 5. Frontier Medical Center, High-tech Zone, Chengdu, Sichuan610213, China.
  • 6. Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan610041, China.
PMID: 42234972 DOI: 10.1021/acs.jmedchem.6c00391
Abstract

The PDZ domain of neuronal nitric oxide synthase (nNOS-PDZ) plays a crucial role in regulating serotonin signaling in the forebrain and has emerged as a promising target for developing rapid-acting antidepressants. Here, we report the identification of N24, a potent and selective small-molecule inhibitor of nNOS-PDZ. N24 induces a substantial thermal shift (ΔTm) of 5.44 °C in a differential scanning fluorimetry (DSF) assay and displays an IC50 of 0.76 ± 0.07 μM in a fluorescence polarization (FP) assay. The cocrystal structure of the nNOS-PDZ-N24 complex reveals key binding interactions. In vivo, N24 produces rapid, dose-dependent antidepressant effects in mouse models of depression induced by chronic unpredictable mild stress (CUMS) and chronic corticosterone treatment, with no evidence of addictive potential or motility-related side effects. Together, these results establish N24 as a potent and selective nNOS-PDZ inhibitor, providing a promising lead compound for the development of antidepressants.

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