Background: Our previous studies showed that α-asaronol was a potential antiepileptic candidate. Here, twelve O-terminus modified ester derivatives of α-asaronol were designed, synthesized and evaluated their anticonvulsant activity.

Methods: All synthetic compounds were subjected to three animal models of seizure (MES, scPTZ and sc3-MP models) combined with neurotoxicity test, as well as the LDH inhibitory test. Furthermore, GABAA Receptor modulation and pharmacokinetic evaluation of compound 4k were also performed.

Results: Five compounds (4a, 4b, 4d, 4e and 4k) showed significant anticonvulsant properties at the dose of 30-300 mg/kg in MES and scPTZ test, but weak activity in sc3-MP model. Meanwhile, 4a, 4b, 4d and 4k showed good LDH inhibitory activity in vitro. Specifically, 4k was the best compound in above evaluation, and better than that of α-asaronol and reference compound (stiripentol). In addition, 4k could increase chloride ion influx by modulating GABAA receptor α1β2γ2 subtype with EC50 of 48.65 ± 10.31 μM and showed good PK profiles in rats with moderate oral bioavailability (51.5%).

Conclusion: These results suggested 4k possesses potential effectiveness in treatment of therapyresistant seizures and is expected to be developed as a novel molecule for safer and efficient anticonvulsants having neuroprotective effects as well as low toxicity.

背景：我们以前的研究表明，α-细辛醇是一种潜在的抗癫痫药。在此，设计，合成和评估了十二种α-细辛醇的O末端修饰的酯衍生物，并评估了其抗惊厥活性。

方法：对所有合成化合物进行三种动物癫痫发作模型（MES，scPTZ和sc3-MP模型），并进行神经毒性试验和LDH抑制试验。此外，还进行了化合物4k的GABAA受体调节和药代动力学评估。

结果：5种化合物（4a，4b，4d，4e和4k）在MES和scPTZ测试中在30-300 mg / kg剂量下显示出显着的抗惊厥特性，但在sc3-MP模型中活性较弱。同时，4a，4b，4d和4k在体外显示出良好的LDH抑制活性。具体而言，4k是上述评估中最好的化合物，并且优于α-细辛醇和参比化合物（stiripentol）。此外，4k可以通过调节GABAA受体α1β2γ2亚型而增加氯离子的流入，EC50为48.65±10.31μM，在中等口服生物利用度（51.5％）的大鼠中表现出良好的PK分布。

结论：这些结果表明4k具有治疗耐药性癫痫的潜在功效，并有望被开发为一种新型分子，用于具有神经保护作用和低毒性的更安全有效的抗惊厥药。