Abstract
A series of 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173 (1b), bearing different nitrogen-containing heterocycles at position-8, were synthesized as AMPA receptor antagonists. All the reported compounds were also biologically evaluated for their binding at glycine/NMDA and KA receptors to better assess their selectivity toward the AMPA receptor. Structure-activity relationships (SAR) on these TQX derivatives have evidenced that the precise positioning of the nitrogen atoms and the specific electronic topography of the 8-heteroaromatic ring are both important for the anchoring to the AMPA receptor. In fact, it has been well-established that the presence of a N(3)-nitrogen-containing heterocycle at position-8 of the TQX framework is an essential feature for potent and selective AMPA receptor antagonists. Functional antagonism at both AMPA receptor and NMDA receptor-ion channel complex was evaluated by assessing the ability of some selected compounds to inhibit depolarization induced by 5 microM AMPA or NMDA in mouse cortical wedge preparations.
MeSH terms
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Animals
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Cerebral Cortex / metabolism
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Cerebral Cortex / physiology
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Cerebral Cortex / ultrastructure
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Electrophysiology
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Excitatory Amino Acid Antagonists / chemical synthesis*
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Excitatory Amino Acid Antagonists / chemistry
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Excitatory Amino Acid Antagonists / metabolism
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Excitatory Amino Acid Antagonists / pharmacology
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In Vitro Techniques
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Ligands
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Male
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Mice
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N-Methylaspartate / antagonists & inhibitors
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N-Methylaspartate / metabolism
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Quinoxalines / chemical synthesis*
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Quinoxalines / chemistry
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Quinoxalines / metabolism
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Quinoxalines / pharmacology
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Rats
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Receptors, Glutamate / drug effects*
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Receptors, Glutamate / metabolism
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Receptors, Kainic Acid / antagonists & inhibitors
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Receptors, Kainic Acid / metabolism
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Structure-Activity Relationship
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Synaptic Membranes / metabolism
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Triazines / chemical synthesis*
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Triazines / chemistry
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Triazines / metabolism
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Triazines / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / antagonists & inhibitors
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism
Substances
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Excitatory Amino Acid Antagonists
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Ligands
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Quinoxalines
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Receptors, Glutamate
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Receptors, Kainic Acid
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TQX 173
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Triazines
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N-Methylaspartate
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid