8-Methylureido-4,5-dihydro-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-10H-imidazo[1,2-a]indeno[1,2-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.
Mignani
S
S
Rhône-Poulenc S.A., Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France. serge.mignani@aventis.com
Bohme
G A
GA
Boireau
A
A
Cheve
M
M
Damour
D
D
Debono
M W
MW
Genevois-Borella
A
A
Imperato
A
A
Jimonet
P
P
Pratt
J
J
Randle
J C
JC
Ribeill
Y
Y
Vuilhorgne
M
M
Stutzmann
J M
JM
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology; D014982:Xenopus laevis
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D011719:Pyrazines; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione; C082309:tezampanel