Quinazolin-4-one alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists: Structure-activity relationship of the C-2 side chain tether

A series of 6-fluoro-3-(2 -chlorophenyl)quinazolin-4-ones has been prepared , which contains a 2-fluorophenyl ring attached to C-2 by a variety of two- atom tethers. These compounds were used to probe the structure-activity rel ationship (SAR) for AMPA receptor inhibition. The relative potencies of the new compounds ranged from 11 nM. to greater than 10 muM. The differential activity of the compounds was rationalized on the basis of alterations of t he 2-fluorophenyl positioning (planar and radial) relative to the quinazoli n-4-one ring based on computational methods. From this effort, new AMPA rec eptor antagonists, containing the methylamino tether group, have been ident ified.