Characterization of the anticonvulsant properties of F-721

Abstract

The anticonvulsant properties of F-721(3-diethylamino-2,2-dimethylpropyl 5[ p-trifluoromethylphenyl]-2furoate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective 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 (ED 50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED 50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED 50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED 50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled 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 seizure severity score to 1.7. The ED 50 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 depolarizing current with a median inhibitory concentration (IC 50) of 1.9 μM. F-721 had no effect on adenosine uptake γ-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.