A Novel Compound QO-83 Alleviates Acute and Chronic Epileptic Seizures in Rodents by Modulating K7 Channel Activity.

AIMS

K7 channels are promising targets for antiepileptic therapy. However, the classic K7 channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel K7 channel opener, QO-83, with good chemical stability and blood-brain barrier penetration, and sought to evaluate its K7-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 K7.2/7.3 channels compared to K7.4 or K7.5 channels. It shows superior efficacy for K7.2 with voltage-dependent opening than retigabine, with W236 identified as the key binding site for the K7.2 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 K7.2 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.