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Volume 17, Number 15, Issue of August 1, 1997 pp. 5760-5771
Copyright ©1997 Society for Neuroscience

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

Received March 14, 1997; revised May 19, 1997; accepted May 20, 1997.

Masayuki Sekiguchi1, Mark W. Fleck2, Mark L. Mayer2, Jiro Takeo3, Yoshiyuki Chiba3, Shinya Yamashita3, and Keiji Wada1

1 Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187, Japan, 2 Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495, and 3 Central Research Laboratory, Nippon Suisan Kaisha Limited, Hachioji, Tokyo 192, Japan

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 µM) dose dependently potentiated glutamate-evoked currents in Xenopus oocytes expressing AMPA (GluRA-GluRD), but not kainate (GluR6 and GluR6+KA2) or NMDA (zeta 1 + epsilon 1-epsilon 4), receptor subunits. PEPA was effective at micromolar concentrations and, in contrast to the action of cyclothiazide, preferentially modulated AMPA receptor flop isoforms. At 200 µM, PEPA potentiated glutamate responses by 50-fold in oocytes expressing GluRCflop (EC50 ~50 µM) 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 µM 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.

Key words: glutamate receptors; AMPA; desensitization; alternative splicing; flip and flop; allosteric modulation




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