CHARACTERIZATION OF THE ANTICONVULSANT PROPERTIES OF F-721

The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpro pyl 5-[p-trifluoromethylphenyl]-2-furoate hydrochloride) were investig ated in a battery of in vivo and in vitro anticonvulsant model systems . After intraperitoneal (ip) administration in mice, F-721 was effecti ve in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures ( ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhi bited only partial activity against clonic seizures induced in the sub cutaneous Metrazol and subcutaneous bicuculline test in mice and was i nactive in this species against tonic seizures induced in the subcutan eous strychnine test. F-721 was effective against MES seizures followi ng oral administration to mice (ED50: 31.3 mg/kg) and only partially e ffective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal e lectroshock model following oral administration (ED50: 9.9 mg/kg). F-7 21 was also effective against corneal-kindled and amygdaloid-kindled s eizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kin dled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizur e severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F- 721 suppressed sustained repetitive firing in response to a depolarizi ng current with a median inhibitory concentration (IC50) of 1.9 muM. F -721 had no effect on adenosine uptake, gamma-aminobutyric acid or NMD A receptor binding. Comparative data from previous studies with clinic ally established antiepileptic agents reveal that F-721's profile of a ctivity most closely resembles that of phenytoin and carbamazepine. Ho wever, F-721 was notably more efficacious in suppressing amygdaloid-ki ndled seizures in rats and was a more potent antagonist of icv NMDA cl onic seizures. Our studies indicate that F-721 is a potent, orally act ive anticonvulsant with a favorable margin of safety. The profile of a nticonvulsant activity of F-721 suggests potential utility in the mana gement of generalized tonic-clonic, simple and complex partial seizure s.