A Novel Compound QO‐83 Alleviates Acute and Chronic Epileptic Seizures in Rodents by Modulating KV7 Channel Activity

ABSTRACT Aims K V 7 channels are promising targets for antiepileptic therapy. However, the classic K V 7 channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel K V 7 channel opener, QO‐83, with good chemical stability and blood–brain barrier penetration, and sought to evaluate its K V 7‐opening activity, antiepileptic effects, and mechanisms of action. Methods We used patch‐clamp electrophysiology, electroencephalogram recordings, dynamic simulations, and various epilepsy models to investigate the mechanisms and antiepileptic activity of QO‐83. Results Compound QO‐83 exhibits greater potency at K V 7.2/7.3 channels compared to K V 7.4 or K V 7.5 channels. It shows superior efficacy for K V 7.2 with voltage‐dependent opening than retigabine, with W236 identified as the key binding site for the K V 7.2 channel. QO‐83 significantly inhibited epileptiform discharge and influenced hippocampal sEPSC and sIPSC amplitudes. QO‐83 has a more effective dose of 1 mg/kg in acute and chronic epilepsy models smaller than that of retigabine (10 mg/kg). The higher potency of QO‐83 may be attributed to its greater stability at the K V 7.2 binding pocket compared to retigabine. Conclusion QO‐83, as a newly developed Kv7.2 opener, has the advantages of stable properties, strong affinity, and high activity compared with retigabine, and is expected to become a new antiepileptic drug.