Synthesis, chiral resolution and pharmacological evaluation of a 2,3-benzodiazepine-derived noncompetitive AMPA receptor antagonist

ChemMedChem. 2009 Mar;4(3):415-20. doi: 10.1002/cmdc.200800341.

Abstract

The resolution of 1-(4-aminophenyl)-3,5-dihydro-3-N-ethylcarbamoyl-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (R,S)-(+/-)-5 by chiral HPLC and assignment of the absolute configuration of the two enantiomers was carried out. Compound (R,S)-(+/-)-5 and its enantiomers were tested in a binding assay to evaluate their affinity for AMPA receptors. Enantiomer (S)-(-)-5 appears to be more potent than its optical antipode (R)-(+)-5. In a primary culture of rat cerebellar granule cells, which express AMPA receptors, (R,S)-(+/-)-5 and (S)-(-)-5 inhibited kainate- induced [Ca(2+)](i) increase, thus confirming the antagonism at the AMPA receptor.

MeSH terms

  • Animals
  • Benzodiazepines / chemical synthesis*
  • Benzodiazepines / chemistry
  • Benzodiazepines / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Computer Simulation
  • Male
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / metabolism*
  • Stereoisomerism

Substances

  • Receptors, AMPA
  • Benzodiazepines