Two metabolites of anticonvulsant U-54494A: their anticonvulsant activity and interaction with sodium channel.
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.
Zhu
Y
Y
Upjohn Company, Kalamazoo, MI 49001.
Im
W B
WB
Lewis
R A
RA
Althaus
J S
JS
Cazers
A R
AR
Nielsen
J W
JW
Palmer
J R
JR
Von Voigtlander
P F
PF
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000494:pharmacology*; D004594:Electrophysiology; D006706:Homeostasis; D008297:Male; D011759:Pyrrolidines / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
D000927:Anticonvulsants; D001549:Benzamides; D003514:Cyclohexylamines; D011759:Pyrrolidines; D015222:Sodium Channels; C080514:N-(2-aminocyclohexyl)-3,4-dichlorobenzamide; C080515:N-(2-methylaminocyclohexyl)-3,4-dichlorobenzamide; C054216:U 54494A