Anticonvulsant activities of phenyl-substituted bicyclic 2,4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel.

Academic Article

Abstract

  • 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.
  • Published In

    Keywords

  • Animals, Anticonvulsants, Binding Sites, Bridged Bicyclo Compounds, Bridged-Ring Compounds, Cerebral Cortex, Drug Evaluation, Preclinical, Mice, Neurons, Oxazoles, Sodium Channels, Structure-Activity Relationship, Synaptosomes
  • Authorlist

  • Brouillette WJ; Brown GB; DeLorey TM; Shirali SS; Grunewald GL
  • Start Page

  • 2218
  • End Page

  • 2221
  • Volume

  • 31
  • Issue

  • 11