Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.
Indeno¿1,2-bpyrazin-2,3-diones have been identified as a novel series of potent ligands on the glycine site of the NMDA receptor. To improve their in vivo activities, an acetic acid-type side chain was introduced to the 5-position, giving water-soluble compounds when formulated as the sodium salt (>10 mg/mL). Introduction of a chlorine atom in the 8-position led to a dramatic improvement of anticonvulsant activity and this was surprising since this change did not improve binding affinity. A plausible explanation is a reduced recognition by a Na(+),K(+)-ATPase active transport system responsible for the excretion of these compounds from the brain and kidney. This promising new chemical series led to the optically active isomer (-)-10i (RPR 118723), a glycine/NMDA antagonist with nanomolar binding affinity and in vivo activity in animal model of convulsions and electrophysiology at doses in the range of 2-3 mg/kg following iv administration.
Jimonet
P
P
Department of Medicinal Chemistry and CNS Program, Aventis Pharma S. A., Centre de Recherche de Vitry-Alfortville, 13 Quai Jules Guesde, BP 14, 94403 Vitry-sur-Seine Cedex, France.
Ribeill
Y
Y
Bohme
G A
GA
Boireau
A
A
Chevé
M
M
Damour
D
D
Doble
A
A
Genevois-Borella
A
A
Herman
F
F
Imperato
A
A
Le Guern
S
S
Manfré
F
F
Pratt
J
J
Randle
J C
JC
Stutzmann
J M
JM
Mignani
S
S
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D013237:Stereoisomerism
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D011719:Pyrazines; C410936:RPR 118723; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate