title: Mechanism of inhibition of the GluA2 AMPA receptor channel opening: consequences of adding an N-3 methylcarbamoyl group to the diazepine ring of 2,3-benzodiazepine derivatives.
abstract: 2,3-Benzodiazepine derivatives are AMPA receptor inhibitors, and they are potential drugs for treating some neurological diseases caused by excessive activity of AMPA receptors. Using a laser-pulse photolysis and rapid solution flow techniques, we characterized the mechanism of action of a 2,3-benzodiazepine derivative, termed BDZ-f, by measuring its inhibitory effect on the channel-opening and channel-closing rate constants as well as the whole-cell current amplitude of the homomeric GluA2Q AMPA receptor channels. We also investigated whether BDZ-f competes with GYKI 52466 for binding to the same site on GluA2Q(flip). GYKI 52466 is the prototypic 2,3-benzodiazepine compound, and BDZ-f is the N-3 methylcarbamoyl derivative. We found that BDZ-f is a noncompetitive inhibitor with a slight preference for the closed-channel state of both the flip and the flop variants of GluA2Q. Similar to other 2,3-benzodiazepine compounds that we have previously characterized, BDZ-f inhibits GluA2Q(flip) by forming an initial, loose intermediate that is partially conducting; however, this intermediate rapidly isomerizes into a tighter, fully inhibitory receptor-inhibitor complex. BDZ-f binds to the same noncompetitive site as GYKI 52466 does. Together, our results show that the addition of an N-3 methylcarbamoyl group to the diazepine ring with the azomethine feature (i.e., GYKI 52466) is what makes BDZ-f more potent and more selective toward the closed-channel conformation than the original GYKI 52466. Our results have useful implications for the structure-activity relationship of the 2,3-benzodiazepine series.
authors.affiliation: Department of Chemistry, and Center for Neuroscience Research, University at Albany, SUNY, Albany, New York 12222, USA.
authors.forename: Congzhou
authors.initials: C
authors.lastname: Wang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Sheng
authors.forename: Li
authors.initials: L
authors.lastname: Niu
mesh_terms: D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D007834:Lasers; D010782:Photolysis; D011485:Protein Binding; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; C118651:GYKI 53784; C104722:glutamate receptor ionotropic, AMPA 2