8-Methylureido-4,5-dihyro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: Highly potent in vivo AMPA antagonists

A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10 H-imidazo[1,2-a]indeno[1,2-e]pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinitie s (IC50 = 4 and 19 nM, respectively) and antagonist properties (IC50 = 2 an d 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-indu ced convulsions in mice after ip, sc and iv administration with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration. (C) 2000 Elsevier Science Ltd. All rights reserved.