D-morphinan Analogs with Favorable Pharmacokinetic Profiles as Dual-Acting Antidepressants

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-02-06 DOI:10.1016/j.ejmech.2025.117349

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

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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.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.