KCNQ channels are proven anti-epileptic drug targets.We took advantage of two strategies to identify novel KCNQ activators.First,a library including 800,000 compounds was screened by a traditional high throughput screening and a series of novel scaffolds were identified.Second,we performed a computer-aid virtual screening targeting the gating charge pathway of KCNQ2 channels.We provided evidence that the gating charge pathway of the voltage-gated KCNQ2 potassium channel can accommodate various small molecule ligands.Additionally,using the KCNQ activators as probes,we found the subtype selectivity of KCNQ channels is dynamically modulated by the membrane lipid,which provide new insight into the action mechanism of KCNQ channels.The identified hits were then evaluated in various of in vivo seizure models.System studies show that HN37 is an effective antiepileptic agent,with high activity,good metabolic characteristics,low toxicity(LD50>1 g/kg)and other notable features in vitro.Pharmacokinetic studies indicate HN37 and its major active metabolites have high distribution rate in brain,long half-life and promising drugablity.HN37 is in preclinical trials.