LY201116 [4-amino-N-(2,6-dimethylphenyl)
benzamide], an effective
anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated
LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and
LY201409 displayed potent
anticonvulsant activity.
LY201409 antagonized maximal electroshock (MES)-induced
seizures with ED50 values of 16.2 and 4.2 mg/kg after
oral administration to mice and rats, respectively. The compound did not effectively antagonize
seizures induced by a variety of chemical
convulsants in rats, but did block
pentylenetetrazol-induced
seizures in mice. Thus, among the classic
anticonvulsants, the profile of
phenytoin most closely resembles that of
LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of
LY201409 that produced CNS side-effects such as sedation or
ataxia were well separated from the anti-MES doses.
LY201409 was a potent, dose-dependent potentiator of
hexobarbital-induced sleeping time in mice.
Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although
LY201409 is a potent and effective
anticonvulsant, it is also one of the most potent potentiators of
hexobarbital-induced sleep time yet described.