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

Nicola Micale, Simona Colleoni, Giovanna Postorino, Alessia Pellicanò, Maria Zappalà, John Lazzaro, Valentina Diana, Alfredo Cagnotto, Tiziana Mennini, Silvana Grasso

Research output: Contribution to journalArticlepeer-review

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 IC50 of 1.6 μM and blocked kainate-induced calcium influx in rat cerebellar granule cells with an IC50 of 6.4 μM. Thus, 5c has the in vitro potential as therapeutic drug in the treatment of various neurological disorders.

Original languageEnglish
Pages (from-to)2200-2211
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number5
DOIs
Publication statusPublished - Mar 1 2008

Keywords

  • 2,3-Benzodiazepin-4-ones
  • AMPAR affinity
  • Binding assay

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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