PT - JOURNAL ARTICLE AU - Paulianda J. Jones AU - Ellen C. Merrick AU - Timothy W. Batts AU - Nicholas J. Hargus AU - Yuesheng Wang AU - James P. Stables AU - Edward H. Bertram AU - Milton L. Brown AU - Manoj K. Patel TI - Modulation of Sodium Channel Inactivation Gating by a Novel Lactam: Implications for Seizure Suppression in Chronic Limbic Epilepsy AID - 10.1124/jpet.108.144709 DP - 2009 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 201--212 VI - 328 IP - 1 4099 - http://jpet.aspetjournals.org/content/328/1/201.short 4100 - http://jpet.aspetjournals.org/content/328/1/201.full SO - J Pharmacol Exp Ther2009 Jan 01; 328 AB - Epilepsy remains a devastating neurological disorder associated with recurrent, unprovoked, spontaneous epileptic seizures. Current treatments involve seizure suppression using antiepileptic drugs (AEDs); however, many patients remain refractory to current treatments or suffer serious side effects. In view of this continued need for more effective and safer AEDs, we have designed a novel compound, 3-hydroxy-3-(4-methoxyphenyl)-1-methyl-1,3-dihydro-indol-2-one (YWI92), based on a lactam structural class, and evaluated its modulation of human neuronal sodium channel isoform (hNav)1.2 currents and hippocampal neuron action potential firing. Furthermore, we have tested its AED activity using a chronic and acute rat seizure model. In a similar manner to lamotrigine, a clinically used AED, YWI92 exhibited tonic block of hNav1.2 channels and caused a hyperpolarizing shift in the steady-state inactivation curve when using a 30-s inactivating prepulse. YWI92 also delayed the time constants of channel repriming after a 30-s inactivating prepulse and exhibited use-dependent block at 20-Hz stimulation frequency. In membrane excitability experiments, YWI92 inhibited burst firing in CA1 neurons of animals with temporal lobe epilepsy at concentrations that had little effect on CA1 neurons from control animals. These actions on neuronal activity translated into AED activity in the maximal electroshock acute seizure model (ED50 = 22.96 mg/kg), and importantly, in a chronic temporal lobe epilepsy model, in which the mean number of seizures was reduced. Notably, YWI92 exhibited no sedative/ataxic side effects at concentrations up to 500 mg/kg. In summary, greater affinity for inactivated sodium channels, particularly after long depolarizing prepulses, may be important for both anticonvulsant activity and drug tolerability. U.S. Government work not protected by U.S. copyright