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

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-03-24 DOI:10.1111/cns.70334

Xiangyu Wang, Yang Zhang, Hui Liu, Jiahao Wang, Boxuan Zhang, Tenghui He, Huiran Zhang, Zhumei Xiong, Xingang Liu, Jincan Li, Weidong Zhao, Xiao Liu, Wei Zhang, Le Yang, Qian Li, Hailin Zhang, Jinlong Qi, Qingzhong Jia

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引用次数: 0

Abstract

Aims

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 However, the classic K_V7 channel opener retigabine has been withdrawn due to severe adverse reactions.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.

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_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.

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.

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.