Synthesis of anticonvulsive AMPA antagonists: 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives

The overstimulation of excitatory amino acid receptors such as the glutamat e AMPA receptor has been implicated in the physiopathogenesis of egilepsy a s well as ill acute and chronic neurodegenerative disorders. An original se ries of readily water soluble 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2 -e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent d erivative 6a exhibited nanomolar binding affinity (IC50=35nM) and antagonis t activity (IC50-6nM) at ionotropic AMPA receptor. This compound also demon strated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED50 values in the 1-3 mg/kg dose range following ip and iv administration. (C) 2001 Elsevier Science Ltd. All rights reserve d.