Synthesis and potent anticonvulsant activities of 4-oxo-imidazo[1,2-a]inden.
The over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a] indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid derivatives. One of these compounds, 4f, exhibited nanomolar binding affinity, potent competitive antagonism at the ionotropic AMPA receptor and a long duration of anticonvulsant activity after administration by parenteral route in vivo.
Pratt
J
J
Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Jimonet
P
P
Bohme
G A
GA
Boireau
A
A
Damour
D
D
Debono
M W
MW
Genevois-Borella
A
A
Randle
J C
JC
Ribeill
Y
Y
Stutzmann
J M
JM
Vuilhorgne
M
M
Mignani
S
S
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D018690:Excitatory Amino Acid Agonists; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009865:Oocytes / Q000187:drug effects; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013997:Time Factors; D014981:Xenopus; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011719:Pyrazines; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid