7-Acetylenic GABA

The use of acetylenic compounds as suicide inhibitors can be illustrated in the case of 7-acetylenic GABA. y-Aminobutyric acid (GABA), an inhibitory neurotransmitter amino acid, modulates various physiological and pathophysiological processes in the central nervous system. Therefore, elevation of brain GABA levels may be beneficial in the treatment of convulsive disease (epilepsy)... 

Indeed, 7-acetylenic GABA was shown to inhibit GABA-T in vitro and to elevate the intracellular levels of GABA in rodent brains in vivo. Additionally, these experiments indicated that, due to the lipophilic character of 7-acetylenic GABA, its penetration... 

Based on this premise, y-acetylenic GABA (IV) waB synthesized (11) and found to be an irreversible inhibitor of GABA-T, in vitro and in vivo (12). Thus, when GABA-T, partially purified from pig brain, is incubated for varying time periods with y-acetylenic GABA, a time-dependent inactivation process is observed which follows pseudo first-order kinetics. Enzyme half lives range from 28 minutes to 9 minutes with concentrations of inhibitor between 0.029 mM and 0.29 mM. Time dependent inactivation is... 

Figure 5. Inhibition of y-aminobutyric acid transaminase by 4-aminohex-5-ynoic acid (y-acetylenic GABA)...

Loscher, W. 1979. GABA in plasma and cerebrospinal fluid of different species. Effects of y-acetylenic GABA, y-vinyl GABA and sodium valproate. J. Neurochem. 32 1587-91. 

SCHEME 3. Postulated mechanism of GABA-T inhibition by y-acetylenic GABA. Reprinted from Reference 20, 1979, with permission from Pergamon Press Ltd, Headington Hill Hall, Oxford 0X3 OBW, UK... 

Unfortunately, y-acetylenic GABA also inhibits other pyridoxal phosphate dependent enzymes such ks glutamic acid decarboxylase, which catalyzes the formation of GABA... 

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