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Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Synthesis and Structure-Activity Relationships of 4,10-Dihydro-4-oxo-4HImidazo[ 1,2-a]Indeno[1,2-e]Pyrazine Derivatives: Highly Potent and Selective AMPA Receptor Antagonists with In Vivo Activity

Author(s): Jean-Marie Stutzmann, Marc Vuilhorgne and Serge Mignani

Volume 4, Issue 2, 2004

Page: [123 - 140] Pages: 18

DOI: 10.2174/1389557043487411

Price: $65

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Abstract

The excitatory neurotransmitter glutamate interacts with ionotropic and metabotropic receptors that mediate a variety of normal signalling processes in the brain. However, excessive stimulation of these receptors appears to be involved in neurodegenerative processes, at least in animal models. Ionotropic glutamate receptors can be divided into NMDA and non-NMDA (AMPA and KA) subtypes on the basis of t heir preferential affinities for the synthetic excitatory aminoacids N-methyl-D-aspartic acid (NMDA) or 2-amino-3- (3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), respectively. Although most of the early evidence favoured a role for NMDA receptors in the excitotoxic processes, it has been recognised that AMPA receptors may also be significantly involved in neuronal death. As a consequence, the synthesis of specific AMPA antagonists has raised much interest as source of potential drugs for epilepsy and acute and chronic neurodegenerative diseases. The discovery of RPR117824, a potent and selective AMPA receptors antagonist endowed with anticonvulsant and neuroprotective properties, induced growing interest on dihydro-4-oxo-4Himidazo[ 1,2-a]indeno[1,2-e]pyrazine series. This review covers the main chemical course leading to the most promising compounds as well as the pharmacological properties of this original class of AMPA receptor antagonists.

Keywords: Dihydro-4-oxo-4HImidazo, propionic acid (AMPA), 3-hydroxy-5-methylisoxazol-4-yl

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