Anticonvulsant activities of 4-(4 '-fluorophenoxy) benzaldehyde semicarbazone

A series of aryloxyaryl semicarbazones had been shown previously to possess significant anticonvulsant activity in the maximal electroshock screen in both rats and mice as well as in the subcutaneous pentylenetetrazol test in mice. One member of this series, namely 4-(4 '-fluorophenoxy) benzaldehyde semicarbazone (Compound IV), was selected for detailed studies with a view to determining whether it should proceed to full-scale preclinical evaluat ion; these results are reported herein. After intraperitoneal injection, Co mpound IV afforded protection in the Frings audiogenic mouse test. In addit ion, it had activity in the rat corneal kindling screen after oral administ ration and in the rat hippocampal kindling screen after intraperitoneal adm inistration, but it was virtually inactive in the amygdala kindling test in rats. When administered by the intravenous route to genetically susceptibl e epileptic chickens, Compound IV and eight analogs prevented convulsions i nduced by alternating strobe lights. Compound IV did not display proconvuls ant properties when examined in the timed intravenous test in mice nor did this compound cause significant effects on liver weights, microsomal protei n yields, and various hepatic enzymes after oral administration to rats. In traperitoneal injection of Compound IV afforded little or no protection to mice who had received subcutaneously convulsive doses of bicuculline, picro toxin, or strychnine. This compound did not elevate gamma-aminobutyric acid levels or inhibit gamma-aminobutyric acid uptake. ion-imaging and electrop hysiological experiments suggested that the mode of action of this compound could be on calcium and sodium channels. In most of these experiments, Com pound IV was superior to the widely used antiepileptic drug phenytoin. (C) 1999 Wiley-Liss, Inc.