IDOR-1104-0086, a novel Kv7 channel activator with antiseizure effects in rodents

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-08-25 DOI:10.1016/j.neuropharm.2025.110658

Melanie Kessler, Andreas Mühlemann , Malgorzata Anna Mis , Romain Siegrist, Swen Seeland , Caroline Deymier, Cary-Ann Mathieu , Hélène Roellinger , Tsvetomira Atanasova , Catherine Roch , Michel Alexander Steiner

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Abstract

A neuronal, phenotypic in vitro screen at Idorsia identified IDOR-1104-0086 as a small molecule with antiseizure effects and drug-like properties. Target deconvolution revealed its mechanism as activating voltage-gated potassium (Kv7) channels, which stabilize the resting membrane potential and modulate cellular excitability.

In the current study, we further investigated IDOR-1104-0086's potency and selectivity profile on Kv7.1–7.5 isoforms and compared it to the known Kv7 channel opener and antiseizure medication retigabine. We studied its effects in the amygdala-kindling and 6 Hz rodent models of focal-onset seizures, the maximal electroshock threshold test of generalized convulsive seizures in mice, and a model of absence-like epilepsy in rats featuring non-convulsive generalized seizures.

IDOR-1104-0086 demonstrated greater potency than retigabine on various Kv7 isoforms, including the brain-specific Kv7.2/3 and Kv7.3/5 heterotetramers, and was inactive on the peripheral Kv7.1 isoform expressed on cardiac myocytes. It reduced focal-onset and generalized convulsive seizures in a dose-dependent manner in the employed models. However, it aggravated non-convulsive seizures similarly to retigabine. Unbound IDOR-1104-0086 plasma concentrations that were well tolerated and efficacious in vivo caused a therapeutically relevant shift of the Kv7.2/3 current activation in whole-cell patch-clamp electrophysiology recordings, consistent with retigabine's effects.

IDOR-1104-0086 is a potent activator of Kv7.2/3 channels that reduces focal-onset and generalized convulsive seizures in rodent models while being well tolerated. Its efficacious Kv7 channel activation properties make it a promising drug candidate for the treatment of drug-resistant epilepsy with focal-onset or generalized convulsive seizures.

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具有抗癫痫作用的新型Kv7通道激活剂IDOR-1104-0086

在Idorsia进行的神经元体外表型筛选发现，IDOR-1104-0086是一种具有抗癫痫作用和药物样特性的小分子。靶反褶积的机制为激活电压门控钾通道，稳定静息膜电位，调节细胞兴奋性。在目前的研究中，我们进一步研究了IDOR-1104-0086对Kv7.1-7.5亚型的效价和选择性，并将其与已知的Kv7通道打开剂和抗癫痫药物雷加滨进行了比较。我们研究了其在杏仁核点燃和6 Hz啮齿动物局灶性癫痫模型、小鼠全身性惊厥发作最大电休克阈值测试以及非惊厥性全身性癫痫大鼠缺席样癫痫模型中的作用。IDOR-1104-0086对多种Kv7异构体（包括脑特异性Kv7.2/3和Kv7.3/5异源四聚体）的效价高于雷沙滨，对心肌细胞上表达的外周Kv7.1异构体无活性。在所采用的模型中，它以剂量依赖的方式减少了局灶性发作和全身性惊厥发作。然而，与雷沙滨相似，它加重了非惊厥性发作。体内耐受良好且有效的未结合的IDOR-1104-0086血浆浓度引起全细胞膜片钳电生理记录中Kv7.2/3电流激活的治疗相关偏移，与雷加滨的作用一致。IDOR-1104-0086是一种有效的Kv7.2/3通道激活剂，可减少啮齿动物模型的局灶性发作和全身性惊厥发作，同时耐受性良好。其有效的Kv7通道激活特性使其成为治疗局灶性或全身性惊厥发作的耐药癫痫的有希望的候选药物。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).