Selective Inhibition of γ-Aminobutyric Acid Aminotransferase by (3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-Amino-5-fluoro-3-phenylpentanoic Acids

Richard B. Silverman, Shrenik M. Nanavati

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(3R,4R),(3S,4S)- and (3R,4S),(3S,4R)-4-amino-5-fluoro-3-phenylpentanoic acid (1a and 1b) were synthesized and studied as selective inactivators of γ-aminobutyric acid (GABA) aminotransferase. Neither compound caused time-dependent inactivation of the enzyme. Neither compound underwent enzyme-catalyzed transamination nor was fluoride ion eliminated from either compound by the enzyme. No 3-phenyllevulinic acid, the product of elimination of HF followed by enamine hydrolysis, was detected. However, both 1a and 1b were competitive reversible inhibitors of GABA aminotransferase; the for la was smaller than the Kmfor GABA. These results suggest that 1a and 1b bind to the active site of GABA aminotransferase, but γ-proton removal does not occur. Whereas (S)-4-amino-5-fluoropentanoic acid (AFPA) is a potent inhibitor of L-glutamic acid decarboxylase (GAD), neither 1a nor 1b at concentrations 40 times the Kiof AFPA caused any detectable competitive inhibition of GAD. Therefore, the incorporation of a phenyl substituent at the 3-position of AFPA confirms selective inhibition of GABA aminotransferase over GAD.

Original languageEnglish (US)
Pages (from-to)931-936
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Mar 1990

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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