title: Mechanism of inhibition of the GluR2 AMPA receptor channel opening by 2,3-benzodiazepine derivatives.
abstract: 2,3-Benzodiazepine derivatives are drug candidates synthesized for potential treatment of various neurodegenerative diseases involving the excessive activity of AMPA receptors. Here we describe a rapid kinetic investigation of the mechanism of inhibition of the GluR2Qflip AMPA receptor channel opening by two 2,3-benzodiazepine derivatives that are structurally similar (BDZ-2 and BDZ-3). Using a laser-pulse photolysis technique with a time resolution of approximately 60 mus, we measured the effects of these inhibitors on both the channel opening rate and the whole-cell current amplitude. We found that both compounds preferably inhibit the open-channel state, although BDZ-2 is a more potent inhibitor in that it inhibits the open-channel state approximately 5-fold stronger than BDZ-3 does. Both compounds bind to the same noncompetitive site. Binding of an inhibitor to the receptor involves the formation of a loose, partially conducting channel intermediate, which rapidly isomerizes to a tighter complex. The isomerization reaction is identified as the main step at which the receptor distinguishes the structural difference between the two compounds. These results suggest that addition of a bulky group at the N-3 position on the diazepine ring, as in BDZ-3, does not alter the mechanism of action, or the site of binding, but does lower the inhibitory potency, possibly due to an unfavorable interaction of a bulky group at the N-3 position with the receptor site. The new mechanistic revelation about the structure-reactivity relationship is useful in designing conformation-specific, more potent noncompetitive inhibitors for the GluR2 AMPA receptor.
authors.affiliation: Department of Chemistry and Center for Neuroscience Research, University at Albany, State University of New York, Albany, New York 12222, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Ritz
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.forename: Li
authors.initials: L
authors.lastname: Niu
mesh_terms: D000465:Algorithms; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D007834:Lasers; D008956:Models, Chemical; D010782:Photolysis; D011485:Protein Binding / Q000187:drug effects; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D001569:Benzodiazepines; D018698:Glutamic Acid; C104722:glutamate receptor ionotropic, AMPA 2