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

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.

A Pertussis Toxin-Sensitive 8-Lipoxygenase Pathway Is Activated by a Nicotinic Acetylcholine Receptor inAplysia Neurons

Acetylcholine (ACh) activates two types of chloride conductances in Aplysia neurons that can be distinguished by their kinetics and pharmacology. One is a rapidly desensitizing current that is blocked by α-conotoxin-ImI and the other is a sustained current that is insensitive to the toxin. These currents are differentially expressed in Aplysia neurons. We report here that neurons that respond to ACh with a sustained chloride conductance also generate 8-lipoxygenase metabolites. The sustained chloride conductance and the activation of 8-lipoxygenase have similar pharmacological profiles. Both are stimulated by suberyldicholine and nicotine, and both are inhibited by α-bungarotoxin. Like the sustained chloride conductance, the activation of 8-lipoxygenase is not blocked by α-conotoxin-ImI. In spite of the similarities between the metabolic and electrophysiological responses, the generation of 8-lipoxygenase metabolites does not appear to depend on the ion current since an influx of chloride ions is neither necessary nor sufficient for the formation of the lipid metabolites. In addition, the application of pertussis toxin blocked the ACh-activated release of arachidonic acid and the subsequent production of 8-lipoxygenase metabolites, yet the ACh-induced activation of the chloride conductance is not dependent on a G protein. Our results are consistent with the idea that the nicotinic ACh receptor that activates the sustained chloride conductance can, independent of the chloride ion influx, initiate lipid messenger synthesis.