Properties of two derivatives of gamma-aminobutyric acid (GABA) capable of abolishing Cardiazol- and bicuculline-induced convulsions in the rat.

The gamma-NH2 function of GABA was blocked with either benzoyl group (BG1) or a pivaloyl (timethylacetyl) group (PG2). The two derivatives of GABA obtained by the synthetic procedure were chemically pure and fully characterized. Both 14C-BG1 and 14C-PG2, unlike 14-C-GABA, are able to penetrate the blood-brain barrier in rats after subcutaneous injection. BG1 reached its highest concentration in brain 5 min after injection and PG2 after 30 min. This difference appears to be related to the different hydrophobic character of the two compounds, measured after experiments of partition in a water ethylacetate system, and to the different rate of diffusion following subcutaneous administration. BG1 abolished pentetrazole- and bicuculine-induced convulsions in rat when injected 5 min before the administration of the convulsants and PG2 had similar effects when injected 30 min before convulsants. BG1 and PG2 had a slight inhibitory effect on GAD and both BG1 and PG2 acted as substrates for the action of proteolytic enzymes that convert the two compounds back to GABA. Toxicity of both BG1 and PG2 was practically undetectable in rat following administration of the compounds up to 1 g/kg. Glutamate oxidation by rat brain mitochondria was not affected by either BG1 or PG2.