Although propofol is most commonly known for its general anesthetic properties, at subanesthetic doses, propofol has been effectively used to suppress seizures during refractory status epilepticus, a mechanism, in part, attributed to the inhibition of neuronal sodium channels. In this study, we have designed and synthesized two novel analogs of propofol, HS245[2-(3-ethyl-4-hydroxy-5-isopropyl-phenyl)-3,3,3-trifluoro-2-hydroxy-propionamide] and HS357 [2-hydroxy-8-(4-hydroxy-3,5-diisopropyl-phenyl)-2-trifluoromethyl-octanoic acid amide], and determined their effects on sodium currents recorded from cultured hippocampal neurons. HS357 had greater affinity for the inactivated state of the sodium channel than propofol and HS245 (0.22 versus 0.74 and 1.2 M, respectively) and exhibited the greatest ratio of affinity for the resting over the inactivated state. HS357 also demonstrated greater use-dependent block and delayed recovery from inactivation in comparison with propofol and HS245. Under currentclamp conditions, action potentials from hippocampal CA1 neurons in slices were evoked by current injection, or following perfusion with a zero Mg 2ϩ /7 mM K ϩ artificial cerebrospinal fluid solution. Propofol and HS357 reduced the number of current-induced action potentials; however, HS357 caused a greater reduction in the number of spontaneous action potentials. Consistent with these electrophysiology studies, propofol and HS357 protected mice against acute seizures in the 6-Hz (22-mA) partial psychomotor model. Efficacious doses of propofol were associated with an impairment of motor coordination as assessed in the rotorod toxicity assay. In contrast, HS357 demonstrated a 2-fold greater protective index than propofol. Thus, propofol analogs represent an important structural class from which not only effective, but also safer, anticonvulsants may be developed.Epilepsy is a neurological disorder that affects approximately 1 to 2% of the population. Treatment of epilepsy focuses on the suppression of seizures via the use of antiepileptic drugs (AEDs) (Browne and Holmes, 2001). First generation AEDs, such as phenytoin, carbamazepine, phenobarbital, and sodium valproate, along with second generation AEDs, such as topiramate, gabapentin, lamotrigine, and zonisamide, offer a wide selection of possible therapeutic treatments for suppression of seizures. Although the number of AEDs has increased, the percentage of patients who fail to be treated successfully remains constant at an alarming 30% (Loscher and Schmidt, 2002). Substantial problems exist with toxicity, resistance, and idiosyncratic reactions in a number of the currently used AEDs (Brodie, 2001), all of which likely contribute to their failure rate. In view of this failure rate, there remains a need for a better understanding of the mechanisms involved in suppression of epileptic seizures with minimal side effects.Voltage-gated sodium channels play an important role in determining neuronal excitability and, therefore, constitute a proven target for the suppressi...