title: Voltage-dependent block of native AMPA receptor channels by dicationic compounds.
abstract: 1. The kinetics of open channel block of GluR2-containing and GluR2-lacking AMPA receptors (AMPAR) by dicationic compounds (IEM-1460, IEM-1754, and IEM-1925) have been studied in rat hippocampal neurones using whole-cell patch clamp recording and concentration-jump techniques. Neurones were isolated from hippocampal slices by vibrodissociation. 2. The dicationic compounds were approximately 100 - 200 times more potent as blockers of GluR2-lacking AMPAR than as blockers of GluR2-containing AMPAR. The subunit specificity of channel block is determined by the blocking rate constant of a dicationic compound, whereas differences in unblocking rate constants account for differences in potency. 3. Hyperpolarization may decrease the block produced by IEM-1460 and IEM-1754 block due to the voltage-dependence of the unblocking rate constants for these compounds. This suggests that dicationic compounds permeate the AMPAR channel at negative membrane potentials. The effect was particularly apparent for GluR2-lacking AMPAR. These findings indicate that the presence of GluR2-subunit(s) in AMPAR hinders the binding of the cationic compounds and their permeation through the channel. 4. The most potent compound tested was IEM-1925. The presence of a phenylcyclohexyl moiety instead of an adamantane moiety, as in IEM-1460 and IEM1754, is probably responsible for the higher potency of IEM-1925. Dicationic compounds are important not only as pharmacological tools, but also as templates for the synthesis of new selective AMPAR blockers which may be potential therapeutic agents.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, Thorez pr., 44, St.-Petersburg, 194223 Russia.
authors.forename: D B
authors.initials: DB
authors.lastname: Tikhonov
authors.forename: M V
authors.initials: MV
authors.lastname: Samoilova
authors.forename: S L
authors.initials: SL
authors.lastname: Buldakova
authors.forename: V E
authors.initials: VE
authors.lastname: Gmiro
authors.forename: L G
authors.initials: LG
authors.lastname: Magazanik
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002412:Cations / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology*; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002412:Cations; D003959:Diamines; D018690:Excitatory Amino Acid Agonists; C110702:IEM 1460; C092754:IEM 1754; C406748:IEM 1925; D000644:Quaternary Ammonium Compounds; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2; D000218:Adamantane; D007608:Kainic Acid