Abstract
This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (+/-)-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca(2+)](i) in a primary culture of rat cerebellar granule cells which express alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (+/-)-5 at the AMPA and N-methyl-d-aspartic acid (NMDA) receptors was also evaluated.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Benzodiazepines / chemical synthesis*
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology
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Benzodiazepinones / chemical synthesis*
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Benzodiazepinones / chemistry
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Benzodiazepinones / pharmacology
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Calcium / metabolism
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Cells, Cultured
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Cerebellum / cytology
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Cerebellum / metabolism
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Chromatography, High Pressure Liquid
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Circular Dichroism
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In Vitro Techniques
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Kainic Acid / pharmacology
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Mice
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Mice, Inbred DBA
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Models, Molecular
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Molecular Conformation
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Prosencephalon / metabolism
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Radioligand Assay
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Rats
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Receptors, AMPA / antagonists & inhibitors*
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Receptors, AMPA / metabolism
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Receptors, N-Methyl-D-Aspartate / metabolism
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Seizures / drug therapy
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Stereoisomerism
Substances
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3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one
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Anticonvulsants
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Benzodiazepinones
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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Benzodiazepines
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Kainic Acid
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Calcium