title: Synthesis, chiral resolution, and enantiopharmacology of a potent 2,3-benzodiazepine derivative as noncompetitive AMPA receptor antagonist.
abstract: 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 [Ca(2+)](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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università di Messina, 98168 Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
authors.forename: Giovanna
authors.initials: G
authors.lastname: Postorino
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Salvatore
authors.initials: S
authors.lastname: Caccamese
authors.forename: Nunziatina
authors.initials: N
authors.lastname: Parrinello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Gabriella
authors.initials: G
authors.lastname: Roda
authors.forename: Frank S
authors.initials: FS
authors.lastname: Menniti
authors.forename: Giovambattista
authors.initials: G
authors.lastname: De Sarro
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D008968:Molecular Conformation; D016548:Prosencephalon / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013237:Stereoisomerism
chemical_list: C508795:3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one; D000927:Anticonvulsants; D001570:Benzodiazepinones; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D001569:Benzodiazepines; D007608:Kainic Acid; D002118:Calcium