Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist

• Published in: Neuropharmacology 2002-02, Vol.42 (2), p.143-153
• Main Authors: Lazzaro, J.T., Paternain, A.V., Lerma, J., Chenard, B.L., Ewing, F.E., Huang, J., Welch, W.M., Ganong, A.H., Menniti, F.S.
• Format: Article
• Language: English
• Subjects: AMPA receptor antagonist; AMPA receptors; Animals; Atropisomer; Biological and medical sciences; Cell Differentiation; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; CP-465,022; DNA, Complementary - genetics; Dose-Response Relationship, Drug; Ganglia, Spinal - cytology; Ganglia, Spinal - drug effects; Glutamatergic system (aspartate and other excitatory aminoacids); Humans; Kainate receptors; Medical sciences; Membrane Potentials - drug effects; Neurons - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Noncompetitive antagonists; Patch-Clamp Techniques; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Rats; Receptors, AMPA - antagonists & inhibitors; Receptors, Kainic Acid - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Transfection; Tumor Cells, Cultured
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/S0028-3908(01)00170-8

The hypothesis that aberrant α-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-3 H-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.