title: Synthesis, chiral resolution and pharmacological evaluation of a 2,3-benzodiazepine-derived noncompetitive AMPA receptor antagonist.
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.
authors.affiliation: Dipartimento Farmaco Chimico, University of Messina, Via le Annunziata, 98168, Messina, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Calabrò
authors.forename: Daniela
authors.initials: D
authors.lastname: Raneri
authors.forename: Paola
authors.initials: P
authors.lastname: Ficarra
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Simona
authors.initials: S
authors.lastname: Colleoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D018091:Receptors, AMPA; D001569:Benzodiazepines