The
anticonvulsant properties of
F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate 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 (ED50s: 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 (ED50: 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 (ED50: 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 ED50 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 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 depolarizing current with a median inhibitory concentration (IC50) of 1.9 microM.
F-721 had no effect on
adenosine uptake,
gamma-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.