Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel.
8,9-Dioxo-6-phenyl-1-aza-7-oxabicyclo[4.2.1]nonane (1) and 9,10-dioxo-7-phenyl-1-aza-8-oxabicyclo[5.2.1]decane (2), examples of anti-Bredt bicyclic 2,4-oxazolidinediones, were investigated as anticonvulsants in mice. Compound 2 was the more potent (anti-MES ED50 = 66 mg/kg), and its in vivo anti-MES effect was consistent with its in vitro potency of binding to the voltage-sensitive sodium channel (IC50 = 160 microM for the inhibition of binding of [3H]BTX-B), suggesting that 2 may be a new class I anticonvulsant. Several partial structures of 2, either monocyclic lactams or monocyclic 2,4-oxazolidinediones, were also evaluated in these assays, but no correlation was observed between sodium channel binding and anti-MES effects. A significant finding was that monocyclic 5-alkyl-5-phenyl-2,4-oxazolidinediones provided relatively potent, nontoxic, broad-spectrum anticonvulsants.
Brouillette
W J
WJ
Department of Chemistry, University of Alabama, Birmingham 35294.
Brown
G B
GB
DeLorey
T M
TM
Shirali
S S
SS
Grunewald
G L
GL
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis*; D002540:Cerebral Cortex / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010080:Oxazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects
D000927:Anticonvulsants; D001643:Bridged Bicyclo Compounds; D001952:Bridged-Ring Compounds; D010080:Oxazoles; D015222:Sodium Channels