Mechanism of inhibition of GluA2 AMPA receptor channel opening by 2,3-benzodiazepine derivatives: Functional consequences of replacing a 7,8-methylenedioxy with a 7,8-ethylenedioxy moiety

Mohammad S. Qneibi, Nicola Micale, Silvana Grasso, Li Niu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

2,3-Benzodiazepine (2,3-BDZ) compounds are a group of AMPA receptor inhibitors and are drug candidates for treating neurological diseases involving excessive AMPA receptor activity. We investigated the mechanism by which GluA2Q flip receptor channel opening is inhibited by two 2,3-BDZ derivatives, i.e., 1-(4-aminophenyl)-3,5-dihydro-7,8-ethylenedioxy-4H-2,3- benzodiazepin-4-one (2,3-BDZ-11-2) and its 1-(4-amino-3-chlorophenyl) analogue (2,3-BDZ-11-4). Both compounds have a 7,8-ethylenedioxy moiety instead of the 7,8-methylenedioxy feature present in the structure of GYKI 52466, the prototypic 2,3-BDZ compound. Using a laser-pulse photolysis approach with a time resolution of ∼60 μs and a rapid solution flow technique, we characterized the effect of the two compounds on the channel opening process of the homomeric GluA2Q flip receptor. We found that both 2,3-BDZ-11-2 and 2,3-BDZ-11-4 are noncompetitive inhibitors with specificity for the closed-channel conformation of the GluA2Q flip receptor. However, 2,3-BDZ-11-4 is ∼10-fold stronger, defined by its inhibition constant for the closed-channel conformation (i.e., K I = 2 μM), than 2,3-BDZ-11-2. From double-inhibitor experiments, we determined that both compounds bind to the same site, but this site is different from two other known, noncompetitive binding sites on the GluA2Q flip receptor previously reported. Our results provide both mechanistic clues to improve our understanding of AMPA receptor regulation and a structure-activity relationship for designing more potent 2,3-BDZ compounds with predictable properties for this new noncompetitive site.

Original languageAmerican English
Pages (from-to)1787-1795
Number of pages9
JournalBiochemistry
Volume51
Issue number8
DOIs
StatePublished - 28 Feb 2012
Externally publishedYes

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