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Targeted inhibition of the astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula could rapidly alleviate depression\u2010like behaviors. A previous study identified Kir4.1 as a promising target for achieving rapid\u2010onset 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\u2010016, resulting in fifty derivatives. Among these,\n                    <jats:bold>JX3212<\/jats:bold>\n                    exhibits the most potent in vitro inhibitory activity against Kir4.1, with acceptable selectivity and excellent brain exposure. Notably, a single administration of\n                    <jats:bold>JX3212<\/jats:bold>\n                    results in rapid\u2010onset antidepressant effects within 1 h in multiple rodent models of depression, with comparable efficacy to (\n                    <jats:italic>S<\/jats:italic>\n                    )\u2010ketamine; this inhibitor\u2010like effect is abolished in mice with tamoxifen\u2010induced conditional Kir4.1 knockout in astrocytes. Additionally,\n                    <jats:bold>JX3212<\/jats:bold>\n                    demonstrates superior safety margins compared to both (\n                    <jats:italic>S<\/jats:italic>\n                    )\u2010ketamine and the conventional antidepressant imipramine in murine behavioral assays. In summary,\n                    <jats:bold>JX3212<\/jats:bold>\n                    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\n                    <jats:bold>JX3212<\/jats:bold>\n                    as a promising therapeutic candidate for major depressive disorder.\n                  <\/jats:p>","DOI":"10.1002\/advs.202509506","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T09:07:36Z","timestamp":1764752856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery of a Novel and Potent Kir4.1 Inhibitor as a Safe and Rapid\u2010Onset Antidepressant Agent in Mice"],"prefix":"10.1002","volume":"13","author":[{"given":"Sisi","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism Frontiers Science Center for Materiobiology and Dynamic Chemistry Shanghai Key Laboratory of New Drug Design School of Pharmacy East China University of Science and Technology  Shanghai 200237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"},{"name":"School of Pharmacy Henan University  Kaifeng 475004 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism Frontiers Science Center for Materiobiology and Dynamic Chemistry Shanghai Key Laboratory of New Drug Design School of Pharmacy East China University of Science and Technology  Shanghai 200237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai 201203 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