Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycinesite of the NMDA receptor with potent in vivo activity

Indeno[1,2-b]pyrazin-2,3-diones have been identified as a novel series of p otent 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-po sition, 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 dra matic 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 promis ing new chemical series led to the optically active isomer (-)-10i (RPR 118 723), 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.