Jean-Claude Aloup

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, is thought to play an important role in a variety of acute and chronic neurological disorders. Consequently, excitatory amino acid antagonists may have an important therapeutic potential in the treatment of these diseases. Glutamate 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 receptors. Blockade of ionotropic AMPA/KA receptors has been shown to prevent cerebral ischemia insult in experimental models. This article describes the synthesis, 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 which showed micromolar affinity at AMPA/KA receptors and competitively inhibited functional responses mediated by these receptors. In mice, 1 had significant anticonvulsive properties and conferred protection against hypobaric hypoxia and KCN intoxication. In rats and gerbils, 1 possesses significant 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 two synthetic pathways in two or three steps with moderate (30%) or good (70%) yields, respectively. Drug Dev. Res. 48:121–129, 1999.