Department of Pharmacology, Medical University of Innsbruck, Peter-Mayr-Str. 1a, 6020, Innsbruck, Austria.
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria.
Neuropharmacology. 2020 Jan 1;162:107754. doi: 10.1016/j.neuropharm.2019.107754. Epub 2019 Aug 30.
Temporal lobe epilepsy (TLE) is the most common type of focal epilepsies, affecting approximately 35 million people worldwide. Despite the introduction of numerous novel antiepileptic drugs during the last decades, the proportion of patients with therapy-resistant TLE is still high. As an impaired cellular chloride homeostasis appears involved in disease pathophysiology, bumetanide, an antagonist to Na-K-Cl cotransporters, gained interest as potential therapeutic option. However, bumetanide induces a strong diuretic effect and displays poor penetration across the blood-brain barrier (BBB). To reduce these unwanted effects, we modified the already described BUM690 by exchanging the allyl-into a trifluoro-ethyl group to yield BUM532. Furthermore, we exchanged the nitrogen for oxygen in the trifluoro-ethyl group to yield BUM97. In the intrahippocampal kainic acid mouse model of TLE BUM532 ± phenobarbital (PB), bumetanide ± PB and PB alone significantly reduced hippocampal paroxysmal discharges (HPDs) but not spike trains. By contrast, treatment with BUM97 suppressed HPDs as well as spike trains dose-dependently, more pronounced compared to the other tested compounds and exerted a synergistic anticonvulsant effect with PB. Moreover, at higher doses BUM97 achieved long-lasting reduction of spike trains. In pentylenetetrazole-induced acute seizures only BUM532 combined with a sub-effective dose of PB increased the seizure threshold. No diuretic effects were observed at any dose of the three derivatives. Our data demonstrate the successful optimization of the pharmacological profile of bumetanide and the potential of the improved derivative BUM97 for the treatment of therapy-resistant TLE, in particular in combinatorial drug regimens with a GABA mimetic.
颞叶癫痫（TLE）是最常见的局灶性癫痫类型，影响全球约 3500 万人。尽管在过去几十年中引入了许多新型抗癫痫药物，但治疗耐药性 TLE 患者的比例仍然很高。由于细胞氯离子稳态受损似乎与疾病病理生理学有关，作为 Na-K-Cl 共转运体的拮抗剂，布美他尼作为潜在的治疗选择引起了关注。然而，布美他尼会引起强烈的利尿作用，并且穿过血脑屏障（BBB）的穿透性差。为了减少这些不良影响，我们通过将烯丙基替换为三氟乙基，对已经描述的 BUM690 进行了修饰，得到了 BUM532。此外，我们将三氟乙基中的氮替换为氧，得到了 BUM97。在 TLE 的海马内海人酸小鼠模型中，BUM532±苯巴比妥（PB）、布美他尼±PB 和 PB 单独治疗均显著减少海马阵发性放电（HPDs），但不减少尖峰波。相比之下，BUM97 以剂量依赖性方式抑制 HPDs 和尖峰波，与其他测试化合物相比更为明显，并与 PB 发挥协同抗惊厥作用。此外，在较高剂量下，BUM97 可实现尖峰波的长期减少。在戊四氮诱导的急性发作中，只有 BUM532 与 PB 的亚有效剂量联合使用才能提高发作阈值。在任何剂量下，三种衍生物均未观察到利尿作用。我们的数据证明了布美他尼的药理学特性得到了成功优化，并且改进的衍生物 BUM97 具有治疗治疗耐药性 TLE 的潜力，特别是在与 GABA 类似物的组合药物方案中。
