TY - JOUR T1 - Characterization of the Binding Site for a Novel Class of Noncompetitive α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonists JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1310 LP - 1317 DO - 10.1124/mol.58.6.1310 VL - 58 IS - 6 AU - Frank S. Menniti AU - Bertrand L. Chenard AU - Mary B. Collins AU - Mary F. Ducat AU - Mark L. Elliott AU - Frank E. Ewing AU - Jianhua I. Huang AU - Kristin A. Kelly AU - John T. Lazzaro AU - Martin J. Pagnozzi AU - James L. Weeks AU - Willard M. Welch AU - W. Frost White Y1 - 2000/12/01 UR - http://molpharm.aspetjournals.org/content/58/6/1310.abstract N2 - 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. ER -