A Novel Allosteric Potentiator of AMPA Receptors: 4-[2-(Phenylsulfonylamino)ethylthio]-2,6-Difluoro-Phenoxyacetamide

• Published in: The Journal of neuroscience 1997-08, Vol.17 (15), p.5760-5771
• Main Authors: Sekiguchi, Masayuki, Fleck, Mark W, Mayer, Mark L, Takeo, Jiro, Chiba, Yoshiyuki, Yamashita, Shinya, Wada, Keiji
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.17-15-05760.1997

We report that a novel sulfonylamino compound, 4-[2-(phenylsulfonylamino)ethylthio]-2,6-difluoro-phenoxyacetamide (PEPA), selectively potentiates glutamate receptors of the AMPA subtype. PEPA (1–200 μ m ) dose dependently potentiated glutamate-evoked currents in Xenopus oocytes expressing AMPA (GluRA–GluRD), but not kainate (GluR6 and GluR6+KA2) or NMDA (ζ1 + ε1–ε4), receptor subunits. PEPA was effective at micromolar concentrations and, in contrast to the action of cyclothiazide, preferentially modulated AMPA receptor flop isoforms. At 200 μ m , PEPA potentiated glutamate responses by 50-fold in oocytes expressing GluRC flop (EC 50 ∼50 μ m ) versus only threefold for GluRC flip ; a similar preference for flop isoforms was observed for other AMPA receptor subunits. Dose–response analysis for GluRC flop revealed that 100 μ m 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.