(ARYLOXY)ARYL SEMICARBAZONES AND RELATED-COMPOUNDS - A NOVEL CLASS OFANTICONVULSANT AGENTS POSSESSING HIGH-ACTIVITY IN THE MAXIMAL ELECTROSHOCK SCREEN

A number of (aryloxy)aryl semicarbazones and related compounds were sy nthesized and evaluated for anticonvulsant activities. After intraperi toneal injection to mice, the semicarbazones were examined in the maxi mal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ), and n eurotoxicity (NT) screens. The results indicated that greater protecti on was obtained in the MES test than the scPTZ screen. Quantitation of approximately one-third of the compounds revealed an average protecti on index (PI, i.e. TD50/ED(50)) Of approximately 9. After oral adminis tration to rats, a number of compounds displayed significant potencies in the MES screen (ED(50) of 1-5 mg/kg) accompanied by very high prot ection indices. In fact over half the compounds had PI figures of grea ter than 100, and two were in excess of 300. The compounds were essent ially inactive in the scPTZ and NT screens after oral administration t o rats. Various compounds displayed greater potencies and PI figures i n the mouse intraperitoneal and rat oral screens than three reference clinically used drugs. The data generated supported a binding site hyp othesis. Quantitative structure-activity relationships indicated a num ber of physicochemical parameters which contributed to activity in the MES screen. X-ray crystallography of five compounds suggested the imp ortance of certain interatomic distances and bond angles for activity in the mouse and rat MES screens.