title: Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist.
abstract: The hypothesis that aberrant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity contributes to epileptogenesis and neurodegeneration has prompted the search for AMPA receptor antagonists as potential therapeutics to treat these conditions. We describe the functional characterization of a novel quinazolin-4-one AMPA receptor antagonist, 3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one (CP-465,022). This compound inhibits AMPA receptor-mediated currents in rat cortical neurons with an IC(50) of 25 nM. Inhibition is noncompetitive with agonist concentration and is not use- or voltage-dependent. CP-465,022 is selective for AMPA over kainate and N-methyl-D-aspartate receptors. However, the compound is found to be equipotent for AMPA receptors composed of different AMPA receptor subunit combinations. This is indicated by the finding that CP-465,022 is equivalently potent for inhibition of AMPA receptor-mediated responses in different types of neurons that express different AMPA receptor subunits. Thus, CP-465,022 provides a new tool to investigate the role of AMPA receptors in physiological and pathophysiological processes.
authors.affiliation: CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Lazzaro
authors.forename: A V
authors.initials: AV
authors.lastname: Paternain
authors.forename: J
authors.initials: J
authors.lastname: Lerma
authors.forename: B L
authors.initials: BL
authors.lastname: Chenard
authors.forename: F E
authors.initials: FE
authors.lastname: Ewing
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: W M
authors.initials: WM
authors.lastname: Welch
authors.forename: A H
authors.initials: AH
authors.lastname: Ganong
authors.forename: F S
authors.initials: FS
authors.lastname: Menniti
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D011799:Quinazolines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C418042:CP 465,022