1] State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2013 Oct;34(10):1359-66. doi: 10.1038/aps.2013.79. Epub 2013 Aug 12.
Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies.
A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System.
A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC50 value=0.10 ± 0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation.
The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors.
瑞替加滨是一种 KCNQ2-5 通道激活剂，目前用于治疗部分发作性癫痫。本研究旨在探索瑞替加滨结构修饰是否可能产生新型 KCNQ2 通道抑制剂，这是 KCNQ 通道研究的有价值工具。
设计并合成了一系列瑞替加滨衍生物。在 CHO 细胞中表达 KCNQ2 通道。使用全细胞膜片钳技术记录 KCNQ2 电流。使用 ALA 8 通道溶液交换系统将测试化合物递送至记录细胞的细胞外液中。
共合成并电生理测试了 23 种瑞替加滨衍生物（HN31-HN410）。在这些化合物中，HN38 是最有效的 KCNQ2 通道抑制剂（IC50 值=0.10±0.05 μmol/L），比经典的 KCNQ 抑制剂 XE991 强 7 倍。进一步分析表明，HN38（3 μmol/L）对通道激活没有可检测的影响，但在超极化电压下加速失活。相比之下，XE991（3 μmol/L）对通道激活和失活动力学没有影响。
瑞替加滨衍生物 HN38 是一种有效的 KCNQ2 抑制剂，其对通道动力学的影响与 XE991 不同。我们的研究为设计和开发有效的 KCNQ2 通道抑制剂提供了新策略。
