 |
 Previous Article | Next Article 
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
( 1 +  1-4), 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
This article has been cited by other articles:
|
|
|
|
 
J.-J. Pang, F. Gao, A. Barrow, R. A. Jacoby, and S. M. Wu
How do tonic glutamatergic synapses evade receptor desensitization?
J. Physiol.,
June 15, 2008;
586(12):
2889 - 2902.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tomita, M. Sekiguchi, K. Wada, R. A. Nicoll, and D. S. Bredt
Stargazin controls the pharmacology of AMPA receptor potentiators
PNAS,
June 27, 2006;
103(26):
10064 - 10067.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Palmer, L. Cotton, and J. M. Henley
The Molecular Pharmacology and Cell Biology of {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptors
Pharmacol. Rev.,
June 1, 2005;
57(2):
253 - 277.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-F. Xia, M. Kessler, and A. C. Arai
Positive {alpha}-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Modulators Have Different Impact on Synaptic Transmission in the Thalamus and Hippocampus
J. Pharmacol. Exp. Ther.,
April 1, 2005;
313(1):
277 - 285.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Seifert, K. Huttmann, J. Schramm, and C. Steinhauser
Enhanced Relative Expression of Glutamate Receptor 1 Flip AMPA Receptor Subunits in Hippocampal Astrocytes of Epilepsy Patients with Ammon's Horn Sclerosis
J. Neurosci.,
February 25, 2004;
24(8):
1996 - 2003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Quirk and E. S. Nisenbaum
Multiple Molecular Determinants for Allosteric Modulation of Alternatively Spliced AMPA Receptors
J. Neurosci.,
November 26, 2003;
23(34):
10953 - 10962.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. W. Fleck, E. Cornell, and S. J. Mah
Amino-Acid Residues Involved in Glutamate Receptor 6 Kainate Receptor Gating and Desensitization
J. Neurosci.,
February 15, 2003;
23(4):
1219 - 1227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Arai, Y.-F. Xia, G. Rogers, G. Lynch, and M. Kessler
Benzamide-Type AMPA Receptor Modulators Form Two Subfamilies with Distinct Modes of Action
J. Pharmacol. Exp. Ther.,
December 1, 2002;
303(3):
1075 - 1085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Arai, Y.-F. Xia, M. Kessler, D. Phillips, R. Chamberlin, R. Granger, and G. Lynch
Effects of 5'-Alkyl-Benzothiadiazides on (R,S)-alpha -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Biophysics and Synaptic Responses
Mol. Pharmacol.,
September 1, 2002;
62(3):
566 - 577.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Baumbarger, M. Muhlhauser, J. Zhai, C. R. Yang, and E. S. Nisenbaum
Positive Modulation of alpha -Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptors in Prefrontal Cortical Pyramidal Neurons by a Novel Allosteric Potentiator
J. Pharmacol. Exp. Ther.,
July 1, 2001;
298(1):
86 - 102.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Lei, B. A. Orser, G. R. L. Thatcher, J. N. Reynolds, and J. F. MacDonald
Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons
J Neurophysiol,
May 1, 2001;
85(5):
2030 - 2038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Rekling, G. D. Funk, D. A. Bayliss, X.-W. Dong, and J. L. Feldman
Synaptic Control of Motoneuronal Excitability
Physiol Rev,
April 1, 2000;
80(2):
767 - 852.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Dingledine, K. Borges, D. Bowie, and S. F. Traynelis
The Glutamate Receptor Ion Channels
Pharmacol. Rev.,
March 1, 1999;
51(1):
7 - 62.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
