title: Structure-activity study of 2,3-benzodiazepin-4-ones noncompetitive AMPAR antagonists: identification of the 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one as neuroprotective agent.
abstract: In the search for AMPA receptor (AMPAR) antagonists, 2,3-benzodiazepines represent a family of specific noncompetitive antagonists with anticonvulsant and neuroprotective properties. We have previously shown that 2,3-benzodiazepin-4-ones possess marked anticonvulsant properties and high affinity for the noncompetitive binding site of the AMPAR complex. In this paper, we report the synthesis and pharmacological characterization of a full set of 2,3-benzodiazepin-4-ones in order to better define the structure-activity relationship (SAR) of this class of compounds. Binding assays and functional tests were performed to evaluate the antagonistic activity at the AMPARs. Through these results we have identified a potent AMPAR antagonist, 1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one (5c). This compound noncompetitively inhibited AMPAR-mediated toxicity in primary mouse hippocampal cultures with an IC(50) of 1.6muM and blocked kainate-induced calcium influx in rat cerebellar granule cells with an IC(50) of 6.4muM. Thus, 5c has the in vitro potential as therapeutic drug in the treatment of various neurological disorders.
authors: Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata, 98168 Messina, Messina, Italy.
authors: Nicola
authors: N
authors: Micale
authors: Simona
authors: S
authors: Colleoni
authors: Giovanna
authors: G
authors: Postorino
authors: Alessia
authors: A
authors: Pellicanò
authors: Maria
authors: M
authors: Zappalà
authors: John
authors: J
authors: Lazzaro
authors: Valentina
authors: V
authors: Diana
authors: Alfredo
authors: A
authors: Cagnotto
authors: Tiziana
authors: T
authors: Mennini
authors: Silvana
authors: S
authors: Grasso
mesh_terms: D000818:Animals; 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; D006624:Hippocampus / Q000166:cytology; D020128:Inhibitory Concentration 50; D007608:Kainic Acid / Q000633:toxicity; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C528604:1-(4-amino-3-methylphenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3-benzodiazepin-4-one; D001570:Benzodiazepinones; D008024:Ligands; D018696:Neuroprotective Agents; D018091:Receptors, AMPA; D001569:Benzodiazepines; D007608:Kainic Acid; D002118:Calcium