Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogs (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [(3)H]-batrachotoxinin-A-20-alpha-benzoate ([(3)H]-BTX-B) displacement yielding IC(50)'s of 22 and 5.7 microM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 microM, compounds 4 and 5 tonically inhibited sodium channels currents by 59+/-7.8% (n=5) and 70+/-7.5% (n=7), respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.