Abstract
N-Acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation
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Animals
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Anticonvulsants / chemical synthesis
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Anticonvulsants / chemistry
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Anticonvulsants / pharmacology
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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 / pharmacology
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Ligands
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Mice
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Mice, Inbred DBA
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Receptors, AMPA / antagonists & inhibitors*
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Receptors, AMPA / physiology
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Seizures / drug therapy
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Seizures / etiology
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Structure-Activity Relationship
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Tetrahydroisoquinolines*
Substances
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2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
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Anticonvulsants
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Excitatory Amino Acid Antagonists
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Isoquinolines
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Ligands
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Receptors, AMPA
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Tetrahydroisoquinolines