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Molecular Pharmacology

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Research ArticleArticle

Characterization of the Binding Site for a Novel Class of Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonists

Frank S. Menniti, Bertrand L. Chenard, Mary B. Collins, Mary F. Ducat, Mark L. Elliott, Frank E. Ewing, Jianhua I. Huang, Kristin A. Kelly, John T. Lazzaro, Martin J. Pagnozzi, James L. Weeks, Willard M. Welch and W. Frost White
Molecular Pharmacology December 2000, 58 (6) 1310-1317; DOI: https://doi.org/10.1124/mol.58.6.1310
Frank S. Menniti
Pfizer Global Research and Development, Groton, Connecticut
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Bertrand L. Chenard
Pfizer Global Research and Development, Groton, Connecticut
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Mary B. Collins
Pfizer Global Research and Development, Groton, Connecticut
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Mary F. Ducat
Pfizer Global Research and Development, Groton, Connecticut
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Mark L. Elliott
Pfizer Global Research and Development, Groton, Connecticut
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Frank E. Ewing
Pfizer Global Research and Development, Groton, Connecticut
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Jianhua I. Huang
Pfizer Global Research and Development, Groton, Connecticut
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Kristin A. Kelly
Pfizer Global Research and Development, Groton, Connecticut
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John T. Lazzaro
Pfizer Global Research and Development, Groton, Connecticut
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Martin J. Pagnozzi
Pfizer Global Research and Development, Groton, Connecticut
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James L. Weeks
Pfizer Global Research and Development, Groton, Connecticut
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Willard M. Welch
Pfizer Global Research and Development, Groton, Connecticut
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W. Frost White
Pfizer Global Research and Development, Groton, Connecticut
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This article has a correction. Please see:

  • Correction - March 01, 2001

Abstract

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is an ionotropic glutamate receptor that mediates fast excitatory synaptic transmission throughout the central nervous system. In addition to the glutamate binding site, allosteric modulatory sites on the receptor are inferred from the ability of synthetic compounds to affect channel function without interaction with the glutamate binding site. We have identified a novel class of potent, noncompetitive AMPA receptor antagonists typified by CP-465,022 and CP-526,427. The latter compound was radiolabeled and used to elucidate the pharmacology of one allosteric modulatory site. [3H]CP-526,427 labels a single binding site in rat forebrain membranes with aK d value of 3.3 nM and aB max of 7.0 pmol/mg of protein. The [3H]CP-526,427 binding site does not seem to interact directly with the glutamate binding site but overlaps with that for another class of AMPA receptor antagonists, the 2,3-benzodiazepines. This binding site is distinct from that for the antagonist Evans blue and for several classes of compounds that modulate AMPA receptor desensitization. These results indicate the existence of at least two physically distinct allosteric sites on the AMPA receptor through which channel activity or desensitization is modulated.

Footnotes

  • Send reprint requests to: Dr. Frank S. Menniti, Pfizer Inc., Eastern Point Road, Groton, CT 06340. E-mail:mennitifs{at}groton.pfizer.com

  • This work was supported by Pfizer, Inc.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (6)
Molecular Pharmacology
Vol. 58, Issue 6
1 Dec 2000
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Research ArticleArticle

Characterization of the Binding Site for a Novel Class of Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonists

Frank S. Menniti, Bertrand L. Chenard, Mary B. Collins, Mary F. Ducat, Mark L. Elliott, Frank E. Ewing, Jianhua I. Huang, Kristin A. Kelly, John T. Lazzaro, Martin J. Pagnozzi, James L. Weeks, Willard M. Welch and W. Frost White
Molecular Pharmacology December 1, 2000, 58 (6) 1310-1317; DOI: https://doi.org/10.1124/mol.58.6.1310

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Research ArticleArticle

Characterization of the Binding Site for a Novel Class of Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonists

Frank S. Menniti, Bertrand L. Chenard, Mary B. Collins, Mary F. Ducat, Mark L. Elliott, Frank E. Ewing, Jianhua I. Huang, Kristin A. Kelly, John T. Lazzaro, Martin J. Pagnozzi, James L. Weeks, Willard M. Welch and W. Frost White
Molecular Pharmacology December 1, 2000, 58 (6) 1310-1317; DOI: https://doi.org/10.1124/mol.58.6.1310
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