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Letters in Drug Design & Discovery

Author(s): Yajun Bai, Bin Li, Jing Xie, Xufei Chen, Shu Cheng, Yujun Bai, Ying Sun, Fanggang Qin, Jing Liang, Yanrui Ding* and Xiaohui Zheng*

DOI: 10.2174/1570180816666191204104127

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Synthesis and Evaluation of α-Asaronol Esters with LDH and GABAA Receptor Modulation as Anticonvulsant Agents

Page: [891 - 904] Pages: 14

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Abstract

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.

Keywords: Drug design, α-asaronol ester derivatives, anticonvulsant, GABAA receptor α1β2γ2, LDH inhibitory, pharmacokinetics.

Graphical Abstract

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