U-54494A, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]
benzamide, has been shown to be a potent and long-acting
anticonvulsant without
analgesic or
sedative effects on intact animals. The persistence of
anticonvulsant activity after a decline in its concentration in the brain implies the conversion of the parent
drug into active metabolites. In this study, two major metabolites of
U-54494A,
U-83892E [cis-N-(2-aminocyclohexyl)-3,4-dichlorobenzamide] and
U-83894A [cis-N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide], were identified. The synthetic metabolites displayed
anticonvulsant activity against electric
shock in experimental animals and blocked
voltage-gated sodium channel in N1E-115
neuroblastoma cells in voltage- and use-dependent manner by interacting with the inactivated channels as well as with the channels in the resting state (like the parent compound). These observations may provide one explanation for the long duration of the
anticonvulsant activity of the parent compound
U-54494A and further underscore the importance of voltage-dependent
sodium channels in neuronal excitability, especially during
seizures.