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
Mini-Reviews in Medicinal Chemistry
Title: 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
Volume: 4 Issue: 2
Author(s): Jean-Marie Stutzmann, Marc Vuilhorgne and Serge Mignani
Affiliation:
Keywords: Dihydro-4-oxo-4HImidazo, propionic acid (AMPA), 3-hydroxy-5-methylisoxazol-4-yl
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.
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Stutzmann Jean-Marie, Vuilhorgne Marc and Mignani Serge, 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, Mini-Reviews in Medicinal Chemistry 2004; 4 (2) . https://dx.doi.org/10.2174/1389557043487411
DOI https://dx.doi.org/10.2174/1389557043487411 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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