γ-氨基丁酸酯。2. γ-氨基丁酸脂质酯的合成、脑摄取及药理特性。

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

作者信息

Jacob J N, Shashoua V E, Campbell A, Baldessarini R J

出版信息

J Med Chem. 1985 Jan;28(1):106-10. doi: 10.1021/jm00379a019.

Abstract

Two lipid esters of U-14C-labeled and unlabeled gamma-aminobutyric acid (GABA) were synthesized to test the possibility that natural lipid analogues, 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 found to be, respectively, 75- and 127-fold greater than that of free GABA. The results indicate that there 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 central nervous system depressant properties by inhibiting the general motor activity of mice. Brain tissue has esterase activity which can release GABA from these compounds. This suggests that these compounds function as "prodrugs" to release GABA in the CNS.

摘要

合成了U-14C标记和未标记的γ-氨基丁酸（GABA）的两种脂质酯，以测试天然脂质类似物（类似于脂质双分子层膜的正常成分）能否穿透血脑屏障并将外源性GABA转运至大脑的可能性。相对于肝脏，发现1-亚麻酸基-2,3-双（4-氨基丁酰基）丙烷-1,2,3-三醇和1,2-二亚麻酸基-3-（4-氨基丁酰基）丙烷-1,2,3-三醇进入小鼠脑内的量分别比游离GABA高75倍和127倍。结果表明，在剂量高达0.36 mmol/kg时，GABA酯分子几乎没有血脑屏障。两种酯化合物，但游离GABA和全身给药的脂质成分均未通过抑制小鼠的一般运动活性表现出中枢神经系统抑制特性。脑组织具有酯酶活性，可从这些化合物中释放GABA。这表明这些化合物作为“前药”在中枢神经系统中释放GABA发挥作用。