IMIDAZOL-1-YL)-7-NITRO-2,3(1H,4H)-QUINOXALINEDIONE HYDROCHLORIDE (YM90K) AND RELATED-COMPOUNDS - STRUCTURE-ACTIVITY-RELATIONSHIPS FOR THE AMPA-TYPE NON-NMDA RECEPTOR

A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their ac tivity to inhibit [H-3]AMPA binding from rat whole brain. From the str ucture-activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) show ed the most potent activity for the AMPA receptor. Compound 11 was eva luated for selectivity versus other excitatory amino acid receptors, a nd its action against AMPA at its receptor in-the rat striatum was cha racterized. These data showed that compound 11 was a selective antagon ist for the AMPA receptor with a K-i value of 0.084 mu M, being approx imately equipotent with; 2,3-dihydro-6-nitro-7-sulfamoylbenzo(f)quinox aline (3) (NBQX;K-i = 0.060 mu M). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).