Biochemical and Electrophysiological Studies on the Mechanism of Action of PNU-151774E, A Novel Antiepileptic Compound

PNU-151774E [(S)-(1)-2-(4-(3-fluorobenzyloxy)benzylamin-o)propanamide methanesulfonate], a new anticonvulsant that dis-plays a wide therapeutic window, has a potency comparable or superior to that of most classic anticonvulsants. PNU-151774E is chemically unrelated to current antiepileptics. In animal seizure models it possesses a broad spectrum of action. In the present study, the action mechanism of PNU-151774E has been investi-gated using electrophysiological and biochemical assays. Binding studies performed with rat brain membranes show that PNU-151774E has high affinity for binding site 2 of the sodium channel receptor, which is greater than that of phenytoin or lamotrigine (IC50, 8 mM versus 47 and 185 mM, respectively). PNU-151774E reduces sustained repetitive firing in a use-dependent manner without modifying the first action potential in hippocampal cul