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Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid-Onset Antidepressant Agent in Mice

文献类型：期刊论文

作者Wang, Sisi3; Zhou, Xiaoyu4; Li, Mengdan2,4; Zhang, Chao3; Xu, Haiyan4; He, Jingyi4; Zhan, Li4; Gu, Yueling4; Gu, Hao3; Tu, Tianyu3
刊名ADVANCED SCIENCE
出版日期2025-12-03
页码14
关键词depression Kir4.1 inhibitors rapid-onset (S)-ketamine structural repurposing
DOI10.1002/advs.202509506
英文摘要Major depressive disorder is a serious psychiatric disorder for which novel and fast-acting antidepressants are required. Targeted inhibition of the astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula could rapidly alleviate depression-like behaviors. A previous study identified Kir4.1 as a promising target for achieving rapid-onset antidepressant effects. The aim of this study is to identify novel Kir4.1 inhibitors with good druggability through structural modification of the lead compound EHop-016, resulting in fifty derivatives. Among these, JX3212 exhibits the most potent in vitro inhibitory activity against Kir4.1, with acceptable selectivity and excellent brain exposure. Notably, a single administration of JX3212 results in rapid-onset antidepressant effects within 1 h in multiple rodent models of depression, with comparable efficacy to (S)-ketamine; this inhibitor-like effect is abolished in mice with tamoxifen-induced conditional Kir4.1 knockout in astrocytes. Additionally, JX3212 demonstrates superior safety margins compared to both (S)-ketamine and the conventional antidepressant imipramine in murine behavioral assays. In summary, JX3212 functions as a selective Kir4.1 inhibitor with favorable druggability and stable antidepressant efficacy in preclinical models. This pharmacological profile supports the further development of JX3212 as a promising therapeutic candidate for major depressive disorder.
WOS关键词LATERAL HABENULA ; POTASSIUM ; ASTROCYTES ; DEPRESSION ; CHANNEL ; MODEL
资助项目National key R&D Program of China[2021YFA0804904] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830403] ; China National Postdoctoral Program for Innovative Talents[BX20240397] ; National Science Fund for Distinguished Young Scholars[82404594] ; China Postdoctoral Science Foundation[2024M753376] ; Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism[03-28] ; Innovative Research Team of High-level Local Universities in Shanghai[SHSMU-ZDCX20212702] ; Chinese Special Fund for State Key Laboratory of Bioreactor Engineering[2060204]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001629481100001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/322172]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Li, Jian; Gao, Zhaobing; Xu, Yixiang
作者单位1.Hainan Univ, Sch Pharmaceut Sci, Minist Educ, Key Lab Trop Biol Resources, Haikou 570228, Peoples R China
2.Henan Univ, Sch Pharm, Kaifeng 475004, Peoples R China
3.East China Univ Sci & Technol, Sch Pharm,Shanghai Key Lab New Drug Design, Frontiers Sci Ctr Materiobiol & Dynam Chem,State K, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Shanghai 200237, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China
6.Shihezi Univ, Sch Pharm, Minist Educ, Key Lab Xinjiang Phytomedicine Resource & Utilizat, Shihezi 832003, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Sisi,Zhou, Xiaoyu,Li, Mengdan,et al. Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid-Onset Antidepressant Agent in Mice[J]. ADVANCED SCIENCE,2025:14.
APA Wang, Sisi.,Zhou, Xiaoyu.,Li, Mengdan.,Zhang, Chao.,Xu, Haiyan.,...&Xu, Yixiang.(2025).Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid-Onset Antidepressant Agent in Mice.ADVANCED SCIENCE,14.
MLA Wang, Sisi,et al."Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid-Onset Antidepressant Agent in Mice".ADVANCED SCIENCE (2025):14.

入库方式： OAI收割

来源：上海药物研究所

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