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

## TL;DR

A new compound, QO-83, was developed to treat epilepsy by targeting KV7 channels more effectively than the withdrawn drug retigabine.

## Contribution

QO-83 is a novel KV7 channel opener with higher potency and better stability than retigabine.

## Key findings

- QO-83 shows greater potency at KV7.2/7.3 channels compared to KV7.4 or KV7.5 channels.
- QO-83 significantly inhibits epileptiform discharges and influences synaptic activity in the hippocampus.
- QO-83 has a more effective dose than retigabine in both acute and chronic epilepsy models.

## Abstract

KV7 channels are promising targets for antiepileptic therapy. However, the classic KV7 channel opener retigabine has been withdrawn due to severe adverse reactions. We developed a novel KV7 channel opener, QO‐83, with good chemical stability and blood–brain barrier penetration, and sought to evaluate its KV7‐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 KV7.2/7.3 channels compared to KV7.4 or KV7.5 channels. It shows superior efficacy for KV7.2 with voltage‐dependent opening than retigabine, with W236 identified as the key binding site for the KV7.2 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 KV7.2 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.

QO‐83 has better opening effects on KV7.2 and KV7.2/7.3 channels, with W236 as the key site for its high binding free energy to KV7.2. By opening KV7 channels, regulating sIPSC and sEPSC amplitudes, and inhibiting epileptiform discharges, QO‐83 outperforms RTG in both acute and chronic epilepsy models.