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

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 9; pp. 1205 - 1210
• Main Authors: Stutzmann, Jean-Marie, Bohme, Georg Andrees, Boireau, Alain, Damour, Dominique, Debono, Marc Williams, Genevois-Borella, Arielle, Jimonet, Patrick, Pratt, Jeremy, Randle, John C.R, Ribeill, Yves, Vuilhorgne, Marc, Mignani, Serge
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 07.05.2001; Elsevier
• Subjects: Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Intraperitoneal administration; Intravenous administration; Rat; Angular nitrogen heterocycle; Central nervous system; Lactam; Anticonvulsant; Glutamate receptor; Structure activity relation; Aromatic compound; Antagonist; Chemical synthesis; Neurological disorder; Rodentia; Tetracyclic compound; In vitro; Vertebrata; Chemotherapy; Experimental disease; AMPA receptor; Mammalia; Treatment; Convulsion; Mouse; Animal; Affinity; Brain (vertebrata)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00180-9

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 (IC 50=35 nM) and antagonist activity (IC 50=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 ED 50 values in the 1–3 mg/kg dose range following ip and iv administration. The 4-oxo-imidazo[1,2- a]indeno[1,2- e]pyrazin-2-carboxylic acid 1 exhibited strong binding affinity for the AMPA receptor (IC 50=35 nM) and potent antagonist activity against electrophysiological responses (IC 50=6 nM). Compound 1 demonstrated also an anticonvulsant effect at low doses in MES test with ED 50 values between 1 and 3 mg/kg dose range following ip and iv administration (mouse) and extended long duration of action following iv administration (mouse and rats).