This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (+/-)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca2+](i) in a primary culture of rat cerebellar granule cells which express alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound ()-5 at the AMPA and N-methyl-D-aspartic acid (NMDA) receptors was also evaluated.
|Titolo:||Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist|
|Autori interni:||GRAZIOSO, GIOVANNI|
|Parole Chiave:||2,3-Benzodiazepine ; AMPA Receptor Antagonist ; Chiral Resolution ;|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||2006|
|Digital Object Identifier (DOI):||10.1021/jm050552y|
|Appare nelle tipologie:||01 - Articolo su periodico|