Voltage-gated Kv7/KCNQ/M-potassium channels play an essential role in setting the resting membrane potential and in controlling the excitability of neurons.Mutation or depression of KCNQ channels results in neuronal hyperactivity and disease.KCNQ function is also indicated in nociceptive sensory systems.Therefore, modulation of KCNQ2/3 function represents a potentially new strategy to treat neuronal excitability disorders such as epilepsy and neuropathic pain.We designed and synthesized a novel serial compounds of pyrazolo[1,5-a] pyrimidin-7(4H)-ones (PPOs) which activate KCNQ channels.Here, in this study, we characterized one of these compounds, QO-58s effect and mechanism underlying the activation of KCNQ channels using patch clamp technique.(1), QO-58 activated KCNQ2/Q3 currents at-40 mV concentration-dependently with a EC50 of 2..3~0.8 M.(2), QO-58 shifted the voltage-dependent activation of the KCNQ2/Q3 channel, and the V1/2 was shifted approximately-40 mV towards more negative potential in the presence 10 M QO-58 (3), QO-58 significantly slowed channel activation and deactivation kinetics.(4), Among KCNQ channels, QO-58 increased homomeric KCNQ1-4 and heteromeric KCNQ3/Q5 currents recorded at-40 mV; the EC50s value were 7.05±1.0, 1.31±1.0, 9.70±2.4, 0.60±0.1, 5.16±2.2 M, for KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ3/Q5, respectively.(5), QO-58 enhanced native M currents from rat DRG neurons.(6), QO-58 dose-dependently prevented seizures induced by electroshock in rats, with a 73.3% reduction of seizures obtained at a dose of 50 mg/kg.The results indicate QO 58 is a potent KCNQ channel opener with more selective effect on KCNQ2 and KCNQ4.QO-58 activates KCNQ channels through enhancing voltage-dependent activation and slowing channel deactivation.QO-58 shows potent anti-seizure effects and can be developed further to treat disease related with neuronal hyperexcitability.