Design and biological evaluation of phenyl-substituted analogs of beta-phenylethylidenehydrazine.
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.
Sowa
Bernard
B
Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada T6G 2R7.
Rauw
Gillian
G
Davood
Asghar
A
Fassihi
Afshin
A
Knaus
Edward E
EE
Baker
Glen B
GB
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D050485:GABA Plasma Membrane Transport Proteins; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D026901:Membrane Transport Proteins / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D050485:GABA Plasma Membrane Transport Proteins; D006834:Hydrazines; D026901:Membrane Transport Proteins; C084776:pheniprazine; D005680:gamma-Aminobutyric Acid