Synthesis and pharmacological properties of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, a new competitive AMPA/KA receptor antagonist

The excessive release of glutamate, a potent excitatory neurotransmitter, i s thought to play an important role in a variety of acute and chronic neuro logical disorders. Consequently, excitatory amino acid antagonists may have an important therapeutic potential in the treatment of these diseases. Glu tamate interacts with at least three types of receptor: 1) NMDA (N-methyl-D -aspartic acid) receptors; 2) AMPA [2-amino-3-(3-hydroxy-5-methylisoxazol-4 -yl)propionic acid]/kainic acid (KA) receptors; and 3) metabotropic recepto rs. Blockade of ionotropic AMPA/KA receptors has been shown to prevent cere bral ischemia insult in experimental models. This article describes the syn thesis, pharmacological activity, and neuroprotective properties of 5H,10H- imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one (1), a novel AMPA/KA antagonist w hich showed micromolar affinity at AMPA/KA receptors and competitively inhi bited functional responses mediated by these receptors. In mice, 1 had sign ificant anticonvulsive properties and conferred protection against hypobari c hypoxia and KCN intoxication. In rats and gerbils, 1 possesses significan t activity in models of global or focal cerebral ischemia, as well as in a model of neurotrauma. Compound 1 was prepared from 2-bromo-indanone using t wo synthetic pathways in two or three steps with moderate (30%) or good (70 %) yields, respectively. (C) 1999 Wiley-Liss, Inc.