Frank E. Ewing

Atropisomeric quinazolin-4-one derivatives are potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists

Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.

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

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.

Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists

Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors.

2-Aryl-1-azabicyclo[2.2.2]octanes as novel nonpeptide substance P antagonists

Abstract The synthesis and SAR of a series of 2-aryl-1-azabicyclo[2.2.2]octanes structurally related to the nonpeptide substance P antagonists CP-96,345 and CP-99,994 are described. The novel SAR observed at the 2-position in these derivatives represents a hybrid between that seen in the two previous series.

Deoxygenation of Pyridones Via Their Tetrazolyl Ethers

Abstract A mild process for the conversion of pyridones to the corresponding pyridines by palladium catalyzed ammonium formate hydrogenolysis of their (1-phenyltetrazol-2-yl) ethers is described.