title: Blockade of NMDA receptor channels by 9-aminoacridine and its derivatives.
abstract: 9-Aminoacridine is known as "foot-in-the-door" NMDA receptor channel blocker because its binding prevents channel closure. Structural determinants of this mechanism of block were studied using a series of 9-aminoacridine derivatives. Experiments were performed on native NMDA receptors of hippocampal pyramidal neurons, isolated from rat brain slices. The use-dependence of block and kinetics of recovery from block were used to characterize mechanism of block produced by the compounds. Modifications, which preserve the flat structure of the tricyclic 9-aminoacridine moiety, affect blocking activity and kinetics but not the foot-in-the-door mechanism. On the contrary, disruption of the flat structure changes the mechanism of block to trapping. It is concluded that flat aromatic structure is one of the critical determinants of the action mechanism of 9-aminoacridine.
authors.affiliation: I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
authors.forename: Oleg I
authors.initials: OI
authors.lastname: Barygin
authors.forename: Valery E
authors.initials: VE
authors.lastname: Gmiro
authors.forename: Kira Kh
authors.initials: KKh
authors.lastname: Kim
authors.forename: Lev G
authors.initials: LG
authors.lastname: Magazanik
authors.forename: Denis B
authors.initials: DB
authors.lastname: Tikhonov
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D015394:Molecular Structure; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013570:Synaptic Membranes / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000585:Aminacrine