2. Academic Validation
  3. D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants

D-morphinan analogs with favorable pharmacokinetic profiles as dual-acting antidepressants

  • Eur J Med Chem. 2025 Apr 5:287:117349. doi: 10.1016/j.ejmech.2025.117349.
Jing Ji 1,  Zhengtao Hu 2,  Fuqiang Zheng 3,  Jiefang Zheng 4,  Jiaxin Cheng 4,  Nuriddinov Zayniddin 4,  Safomuddin Abduahadi 4,  Guan Wang 5,  Xudong Gong 5,  Libiao Pan 5,  Pengcheng Li 5,  Jiangyu Zhao 1,  Tianwen Hu 5,  Weiliang Zhu 4,  Jingshan Shen 4,  Guanghui Tian 5,  Haji Akber Aisa 6,  Yang He 4
Affiliations

Affiliations

  • 1 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 School of Life Science and Technology, Shanghai Tech University, 201210, Shanghai, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 Vigonvita Shanghai Co., Ltd., Shanghai, 201210, China.
  • 6 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; School of Pharmacy, Xinjiang Medical University, Urumqi, 830054, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
PMID: 39952098 DOI: 10.1016/j.ejmech.2025.117349
Abstract

Dextromethorphan (DM) is a dual inhibitor of NMDAR and SERT (IC50 (NMDAR): IC50 (SERT) = 31), but lacks therapeutic clinical value for the treatment of depression due to its low exposure in the human body. In this study, a series of d-morphinan derivatives were designed, synthesized and evaluated both in vitro and in vivo to identify dual inhibitors with improved metabolic stability. Structure-activity relationship studies revealed that a methyl group at the morphinan N-17 position is essential for maintaining SERT activity. Amino-morphinan compounds 24 and 27 exhibited moderate yet more balanced inhibitory activity against both NMDAR and SERT (1< IC50(NMDAR): IC50(SERT) < 5). Compared to DM, compound 24 demonstrated favorable metabolic stability and higher plasma exposure. In vivo, 24 showed significant antidepressant-like effects in the forced swim test in mice after acute administration.

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