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
  • 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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