8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: highly potent in vivo AMPA antagonists |
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Authors: | Mignani S Bohme G A Boireau A Cheve M Damour D Debono M W Genevois-Borella A Imperato A Jimonet P Pratt J Randle J C Ribeill Y Vuilhorgne M Stutzmann J M |
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Institution: | Rh?ne-Poulenc S.A., Rh?ne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France. serge.mignani@aventis.com |
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Abstract: | A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo1,2-a]indeno1,2-e]++ +pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinities (IC50=4 and 19 nM, respectively) and antagonist properties (IC50 = 2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration. |
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