.gamma.-Aminobutyric acid esters. I. Synthesis, brain uptake, and pharmacological studies of aliphatic and steroid esters of .gamma.-aminobutyric acid

Abstract

Labeled and unlabeled aliphatic and steroid esters of [U-14C]GABA were synthesized and tested for their capacity to penetrate the blood-brain barrier and for evidence of central neuropharmacological activity in rodents. The uptake of the labeled 9,12,15-octadecatrienyl (linolenyl), 3-cholesteryl, 1-butyl and the 9-fluoro-11.beta.,17-dihydroxy-16.alpha.-methyl-3,20-dioxopregna-1,4-dien-21-yl (dexamethasone) esters of GABA into mouse brain increased 2-, 25-, 74- and 81-fold over GABA, respectively. The cholesteryl ester of GABA depressed the general motor activity of mice and rats in a dose-dependent manner, whereas the 1-butyl, linolenyl and dexamethasone esters were inactive by this test. Studies of the rates of hydrolysis, GABA receptor binding capacity and octanol/water partition coefficients indicated that pharmacological activity of the esters after entry into the CNS was dependent on their capacity to release GABA by enzymatic hydrolysis and their lipid solubility.