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.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Lazzaro JT,Paternain AV,Lerma J,Chenard BL,Ewing FE,Huang J,Welch WM,Ganong AH,Menniti FS

doi

10.1016/s0028-3908(01)00170-8

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

143-53

issue

2

eissn

0028-3908

issn

1873-7064

pii

S0028390801001708

journal_volume

42

pub_type

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