Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 13, Issue 14, Pages 4389-4395Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2005.04.072
Keywords
beta-phenylethylidenehydrazine; 7-aminobutyric acid; GABA transaminase; glutamine
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beta-Phenylethylidenehydrazine (PEH) has been demonstrated previously to be an inhibitor of gamma-aminobutyric acid transaminase (GABA-T) and to cause a marked increase in rat brain levels of GABA, a major neurotransmitter. A group of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the 2-, 3-, and 4-positions of the phenyl ring, were synthesized for evaluation as inhibitors of GABA-T. The details of the synthesis and chemical characterization of the analogs are described. Preliminary in vitro screening for GABA-T inhibition showed that all the analogs possessed activity against this enzyme, although substitution of CF3 at the 2- and 4-positions caused reduced activity. One of the drugs, 4-fluoro-beta-phenylethylidenehydrazine, was investigated further ex vivo, where it was shown to inhibit GABA-T, elevate brain levels of GABA, and decrease levels of glutamine, similar to the profile observed previously for PEH. (c) 2005 Elsevier Ltd. All rights reserved.
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