A Novel Compound QO-83 Alleviates Acute and Chronic Epileptic Seizures in Rodents by Modulating K_V7 Channel Activity

K_V7 channels are promising targets for antiepileptic therapy. However, the classic K_V7 channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel K_V7 channel opener, QO-83, with good chemical stability and blood-brain barrier penetration, and sought to evaluate its K_V7-opening activity, antiepileptic effects, and mechanisms of action.

We used patch-clamp electrophysiology, electroencephalogram recordings, dynamic simulations, and various epilepsy models to investigate the mechanisms and antiepileptic activity of QO-83.

Compound QO-83 exhibits greater potency at K_V7.2/7.3 channels compared to K_V7.4 or K_V7.5 channels. It shows superior efficacy for K_V7.2 with voltage-dependent opening than retigabine, with W236 identified as the key binding site for the K_V7.2 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_V7.2 binding pocket compared to retigabine.

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.