文献类型：期刊文献

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

作者：Wang, Sisi[1];Zhou, Xiaoyu[2];Li, Mengdan[2,3];Zhang, Chao[1];Xu, Haiyan[2];He, Jingyi[2];Zhan, Li[2];Gu, Yueling[2];Gu, Hao[1];Tu, Tianyu[1];Liu, Hanfang[1];Lu, Taotao[1];Zheng, Yueming[2];Li, Jian[1,4,5];Gao, Zhaobing[2,3,6];Xu, Yixiang[1]

机构：[1]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;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[3]Henan Univ, Sch Pharm, Kaifeng 475004, Peoples R China;[4]Hainan Univ, Sch Pharmaceut Sci, Minist Educ, Key Lab Trop Biol Resources, Haikou 570228, Peoples R China;[5]Shihezi Univ, Sch Pharm, Minist Educ, Key Lab Xinjiang Phytomedicine Resource & Utilizat, Shihezi 832003, Peoples R China;[6]Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528437, Peoples R China

年份：2026

卷号：13

期号：9

外文期刊名：ADVANCED SCIENCE

收录：;EI(收录号：20254919658013);WOS:【SCI-EXPANDED(收录号:WOS:001629481100001)】；

基金：This work was supported by the National key R&D Program of China (2021YFA0804904, to J.L.), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0830403, to Z.G.), China National Postdoctoral Program for Innovative Talents (BX20240397, to X.Z.), National Science Fund for Distinguished Young Scholars (82404594, to X.Z.), China Postdoctoral Science Foundation (2024M753376, to X.Z.), Shanghai Frontier Science Center of Optogenetic Techniques for Cell Metabolism (2021 Sci & Tech 03-28, to J.L.), Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212702, to J.L.), Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204, J.L.).

语种：英文

外文关键词：depression; Kir4.1 inhibitors; rapid-onset; (S)-ketamine; structural repurposing

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.