Abstract
In our studies on the development of new anticonvulsants, we planned the synthesis of N-substituted 1,2,3,4-tetrahydroisoquinolines to explore the structure-activity relationships. All derivatives were evaluated against audiogenic seizures in DBA/2 mice, and the 1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl) derivative (26) showed the highest activity with a potency comparable to that of talampanel, the only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist in clinical trials as an anticonvulsant agent. Electrophysiological experiments indicated that 26 acts as noncompetitive AMPA receptor modulator.
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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In Vitro Techniques
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Isoquinolines / chemical synthesis*
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Isoquinolines / chemistry
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Isoquinolines / pharmacology
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Male
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Mice
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Mice, Inbred DBA
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Olfactory Pathways / drug effects
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Olfactory Pathways / physiology
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Rats
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Rats, Wistar
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Receptors, AMPA / drug effects
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Receptors, AMPA / physiology
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Seizures / etiology
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Seizures / prevention & control
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Structure-Activity Relationship
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Tetrahydroisoquinolines / chemical synthesis*
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Tetrahydroisoquinolines / chemistry
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Tetrahydroisoquinolines / pharmacology
Substances
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1-(4'-bromophenyl)-6,7-dimethoxy-2-(piperidin-1-ylacetyl)-1,2,3,4-tetrahydroisoquinoline
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Anticonvulsants
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Isoquinolines
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Piperidines
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Receptors, AMPA
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Tetrahydroisoquinolines