.gamma.-Aminobutyric acid esters. 2. Synthesis, brain uptake, and pharmacological properties of lipid esters of .gamma.-aminobutyric acid

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Abstract
Two lipid esters of U-14C-labeled and unlabeled GABA were synthesized to test the possibility that natural lipid analogs, which resemble normal components of lipid bilayer membranes, can penetrate the blood-brain barrier and transport exogenous GABA to the brain. The uptake of 1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol and 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol into mouse brain relative to liver was, respectively, 75- and 127-fold greater than that of free GABA. There evidently is little or no blood-brain barrier for the GABA ester molecules at doses up to 0.36 mmol/kg. Both ester compounds, but neither free GABA nor the lipid components delivered systemically, demonstrated CNS depressant properties by inhibiting the general motor activity of mice. Brain tissue has esterase activity which can release GABA from these compounds. These compounds apparently function as prodrugs to release GABA in the CNS.