In:
Letters in Drug Design & Discovery, Bentham Science Publishers Ltd., Vol. 17, No. 7 ( 2020-07-07), p. 891-904
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1570-1808
DOI:
10.2174/1570180816666191204104127
Language:
English
Publisher:
Bentham Science Publishers Ltd.
Publication Date:
2020
SSG:
15,3
Permalink