Two metabolites of anticonvulsant U-54494A: their anticonvulsant activity and interaction with sodium channel
| Autor: | Alexander R. Cazers, Richard A. Lewis, Yu Zhu, Wha-Bin Im, John R. Palmer, John S. Althaus, Philip F. Von Voigtlander, James W. Nielsen |
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| Rok vydání: | 1993 |
| Předmět: |
Male
Pyrrolidines Metabolite medicine.medical_treatment Sodium chemistry.chemical_element Pharmacology Sodium Channels Rats Sprague-Dawley chemistry.chemical_compound medicine Animals Homeostasis Patch clamp Benzamide Molecular Biology Active metabolite Membrane potential Cyclohexylamines General Neuroscience Sodium channel Rats Electrophysiology Anticonvulsant chemistry Benzamides Anticonvulsants Neurology (clinical) Developmental Biology |
| Zdroj: | Brain Research. 606:50-55 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/0006-8993(93)91568-d |
| Popis: | 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 9 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. |
| Databáze: | OpenAIRE |
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