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

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.