title: A novel allosteric potentiator of AMPA receptors: 4--2-(phenylsulfonylamino)ethylthio--2,6-difluoro-phenoxyaceta mide.
abstract: We report that a novel sulfonylamino compound, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetam ide (PEPA), selectively potentiates glutamate receptors of the AMPA subtype. PEPA (1-200 microM) dose dependently potentiated glutamate-evoked currents in Xenopus oocytes expressing AMPA (GluRA-GluRD), but not kainate (GluR6 and GluR6+KA2) or NMDA (zeta1 + epsilon1-epsilon4), receptor subunits. PEPA was effective at micromolar concentrations and, in contrast to the action of cyclothiazide, preferentially modulated AMPA receptor flop isoforms. At 200 microM, PEPA potentiated glutamate responses by 50-fold in oocytes expressing GluRCflop (EC50 approximately 50 microM) versus only threefold for GluRCflip; a similar preference for flop isoforms was observed for other AMPA receptor subunits. Dose-response analysis for GluRCflop revealed that 100 microM PEPA produced a sevenfold increase in AMPA receptor affinity for glutamate. PEPA produced considerably weaker potentiation of kainate-evoked than glutamate-evoked currents, suggesting modulation of the process of receptor desensitization. In human embryonic kidney 293 cells transfected with AMPA receptor subunits, PEPA either abolished or markedly slowed the rate of onset of desensitization and potentiated steady-state equilibrium currents evoked by glutamate with subunit (GluRC >/= GluRD > GluRA) and splice-variant (flop > flip) selectivity similar to that observed in oocytes. Our results show that PEPA is a novel, flop-preferring allosteric modulator of AMPA receptor desensitization at least 100 times more potent than aniracetam.
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: M W
authors.initials: MW
authors.lastname: Fleck
authors.forename: M L
authors.initials: ML
authors.lastname: Mayer
authors.forename: J
authors.initials: J
authors.lastname: Takeo
authors.forename: Y
authors.initials: Y
authors.lastname: Chiba
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Wada
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D009865:Oocytes; D010642:Phenoxyacetates / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000187:drug effects*; D014981:Xenopus
chemical_list: C108189:4-(2-(phenylsulfonylamino)ethylthio)-2,6-difluorophenoxyacetamide; D010642:Phenoxyacetates; D018091:Receptors, AMPA; D018698:Glutamic Acid; D007608:Kainic Acid