Abstract
On the basis of the structures of several potent inhibitor molecules for gamma-aminobutryric acid aminotransferase (GABA-AT) that were previously reported, six modified fluorine-containing conformationally restricted analogues were designed, synthesized, and tested as GABA-AT inhibitors. The syntheses of all six molecules followed from a readily synthesized ketone intermediate. Three of the molecules were found to be irreversible inhibitors of GABA-AT with comparable or larger k(inact)/K(I) values than that of vigabatrin, a clinically used antiepilepsy drug, and the other three were reversible inhibitors. A possible mechanism for inactivation by one of the inactivators is proposed.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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4-Aminobutyrate Transaminase / antagonists & inhibitors*
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4-Aminobutyrate Transaminase / chemistry*
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Animals
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Anticonvulsants / chemistry
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Fluorine*
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Heptanes / chemical synthesis*
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Heptanes / chemistry
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Kinetics
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Molecular Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Swine
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Vigabatrin / chemistry
Substances
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Anticonvulsants
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclopentanes
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Heptanes
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Fluorine
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4-Aminobutyrate Transaminase
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Vigabatrin