Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
Epilepsia. 2021 Jul;62(7):1744-1758. doi: 10.1111/epi.16932. Epub 2021 Jun 4.
About one third of all patients with epilepsy have pharmacoresistant seizures. Thus there is a need for better pharmacological treatments. The human voltage-gated potassium (hK ) channel hK 7.2/7.3 is a validated antiseizure target for compounds that activate this channel. In a previous study we have shown that resin acid derivatives can activate the hK 7.2/7.3 channel. In this study we investigated if these channel activators have the potential to be developed into a new type of antiseizure drug. Thus we examined their structure-activity relationships and the site of action on the hK 7.2/7.3 channel, if they have unwanted cardiac and cardiovascular effects, and their potential antiseizure effect.
Ion channels were expressed in Xenopus oocytes or mammalian cell lines and explored with two-electrode voltage-clamp or automated patch-clamp techniques. Unwanted vascular side effects were investigated with isometric tension recordings. Antiseizure activity was studied in an electrophysiological zebrafish-larvae model.
Fourteen resin acid derivatives were tested on hK 7.2/7.3. The most efficient channel activators were halogenated and had a permanently negatively charged sulfonyl group. The compounds did not bind to the sites of other hK 7.2/7.3 channel activators, retigabine, or ICA-069673. Instead, they interacted with the most extracellular gating charge of the S4 voltage-sensing helix, and the effects are consistent with an electrostatic mechanism. The compounds altered the voltage dependence of hK 7.4, but in contrast to retigabine, there were no effects on the maximum conductance. Consistent with these data, the compounds had less smooth muscle-relaxing effect than retigabine. The compounds had almost no effect on the voltage dependence of hK 11.1, hNa 1.5, or hCa 1.2, or on the amplitude of hK 11.1. Finally, several resin acid derivatives had clear antiseizure effects in a zebrafish-larvae model.
The described resin acid derivatives hold promise for new antiseizure medications, with reduced risk for adverse effects compared with retigabine.
约三分之一的癫痫患者存在药物难治性癫痫发作。因此，需要更好的药物治疗。人类电压门控钾（hK）通道 hK 7.2/7.3 是一种经证实的抗癫痫靶点，可用于激活该通道的化合物。在之前的研究中，我们已经表明树脂酸衍生物可以激活 hK 7.2/7.3 通道。在这项研究中，我们研究了这些通道激活剂是否有可能开发成一种新型抗癫痫药物。因此，我们研究了它们的结构-活性关系以及在 hK 7.2/7.3 通道上的作用部位，如果它们有不良的心脏和心血管作用，以及它们的潜在抗癫痫作用。
离子通道在非洲爪蟾卵母细胞或哺乳动物细胞系中表达，并通过双电极电压钳或自动膜片钳技术进行研究。使用等长张力记录研究了不良的血管副作用。抗癫痫活性在电生理学斑马鱼幼虫模型中进行了研究。
对 14 种树脂酸衍生物在 hK 7.2/7.3 上进行了测试。最有效的通道激活剂是卤素取代的，并带有一个永久带负电荷的磺酰基。这些化合物不与其他 hK 7.2/7.3 通道激活剂、瑞替加滨或 ICA-069673 的结合部位结合。相反，它们与 S4 电压感应螺旋的最外部分子电荷相互作用，其作用与静电机制一致。这些化合物改变了 hK 7.4 的电压依赖性，但与瑞替加滨不同，它们对最大电导没有影响。与这些数据一致的是，与瑞替加滨相比，这些化合物对平滑肌松弛的影响较小。这些化合物对 hK 11.1、hNa 1.5 或 hCa 1.2 的电压依赖性几乎没有影响，也没有影响 hK 11.1 的幅度。最后，几种树脂酸衍生物在斑马鱼幼虫模型中具有明显的抗癫痫作用。
所描述的树脂酸衍生物有望成为新的抗癫痫药物，与瑞替加滨相比，不良反应风险降低。
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