Title of article :
Synthesis of anticonvulsive AMPA antagonists: 4-Oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives
Author/Authors :
Jean-Marie Stutzmann، نويسنده , , Georg Andrees Bohme، نويسنده , , Alain Boireau، نويسنده , , Dominique Damour، نويسنده , , Marc-Williams Debono، نويسنده , , Arielle Genevois-Borella، نويسنده , , Patrick Jimonet، نويسنده , , Jeremy Pratt، نويسنده , , John C. R. Randle، نويسنده , , Yves Ribeill، نويسنده , , Marc Vuilhorgne، نويسنده , , Serge Mignani، نويسنده ,
Abstract :
The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series 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 derivative 6a exhibited nanomolar binding affinity (IC50=35 nM) and antagonist activity (IC50=6 nM) at ionotropic AMPA receptor. This compound also demonstrated 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.
