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

Jing Ji; Zhengtao Hu; Fuqiang Zheng; Jiefang Zheng; Jiaxin Cheng; Nuriddinov Zayniddin; Safomuddin Abduahadi; Guan Wang; Xudong Gong; Libiao Pan; Pengcheng Li; Jiangyu Zhao; Tianwen Hu; Weiliang Zhu; Jingshan Shen; Guanghui Tian; Haji Akber Aisa; Yang He

doi:10.1016/j.ejmech.2025.117349

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. Epub 2025 Feb 6.

Authors

Jing Ji¹, Zhengtao Hu², Fuqiang Zheng³, Jiefang Zheng⁴, Jiaxin Cheng⁴, Nuriddinov Zayniddin⁴, Safomuddin Abduahadi⁴, Guan Wang⁵, Xudong Gong⁵, Libiao Pan⁵, Pengcheng Li⁵, Jiangyu Zhao¹, Tianwen Hu⁵, Weiliang Zhu⁴, Jingshan Shen⁴, Guanghui Tian⁵, Haji Akber Aisa⁶, Yang He⁴

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 (IC_{50 (NMDAR)}: IC_{50 (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< IC_50(NMDAR): IC_50(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.

MeSH terms

Animals
Antidepressive Agents* / chemical synthesis
Antidepressive Agents* / chemistry
Antidepressive Agents* / pharmacokinetics
Antidepressive Agents* / pharmacology
Depression / drug therapy
Dose-Response Relationship, Drug
Humans
Male
Mice
Molecular Structure
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism
Serotonin Plasma Membrane Transport Proteins / metabolism
Structure-Activity Relationship

Substances

Antidepressive Agents
Receptors, N-Methyl-D-Aspartate
Serotonin Plasma Membrane Transport Proteins