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

Abstract

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 evaluation; these results are reported herein. After intraperitoneal injection, Compound IV afforded protection in the Frings audiogenic mouse test. In addition, it had activity in the rat corneal kindling screen after oral administration and in the rat hippocampal kindling screen after intraperitoneal administration, but it was virtually inactive in the amygdala kindling test in rats. When administered by the intravenous route to genetically susceptible epileptic chickens, Compound IV and eight analogs prevented convulsions induced by alternating strobe lights. Compound IV did not display proconvulsant properties when examined in the timed intravenous test in mice nor did this compound cause significant effects on liver weights, microsomal protein yields, and various hepatic enzymes after oral administration to rats. Intraperitoneal injection of Compound IV afforded little or no protection to mice who had received subcutaneously convulsive doses of bicuculline, picrotoxin, or strychnine. This compound did not elevate γ-aminobutyric acid levels or inhibit γ-aminobutyric acid uptake. Ion-imaging and electrophysiological experiments suggested that the mode of action of this compound could be on calcium and sodium channels. In most of these experiments, Compound IV was superior to the widely used antiepileptic drug phenytoin. Drug Dev. Res. 46:112–125, 1999. © 1999 Wiley-Liss, Inc.