Synthesis, brain uptake, and pharmacological properties of a glyceryl lipid containing GABA and the GABA-T inhibitor .gamma.-vinyl-GABA

• Published in: Journal of medicinal chemistry Vol. 33; no. 2; pp. 733 - 736
• Main Authors: Jacob, James N, Hesse, Gary W, Shashoua, Victor E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.02.1990
• Subjects: 4-Aminobutyrate Transaminase - antagonists & inhibitors; Aminocaproates - administration & dosage; Animals; Anticonvulsants - chemical synthesis; Blood-Brain Barrier; Brain - metabolism; Chemistry; Electrophysiology; Exact sciences and technology; gamma-Aminobutyric Acid - administration & dosage; Hippocampus - drug effects; Hippocampus - metabolism; In Vitro Techniques; Lipids; Motor Activity - drug effects; Organic chemistry; Preparations and properties; Prodrugs - chemical synthesis; Prodrugs - metabolism; Rats; Triglycerides; Vigabatrin; Gabaergic receptor; GABA; Enzyme inhibitor; 4-Aminobutyrate aminotransferase; Biological activity; Glyceride
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00164a042

1-O-Linolenoyl-2-O-(4-aminobutyryl)-3-O-(4-vinyl-4-aminobutyryl)glycerol (LGV) was synthesized as an example of a prodrug which readily penetrates the blood-brain barrier (brain penetration index 97% +/- 15%) and releases two active substances in the central nervous system (CNS): GABA (4-aminobutanoic acid) and the GABA transaminase inhibitor (GABA-T) of GABA breakdown. In vitro studies showed that the compound can inhibit GABA-T after hydrolysis by CNS esterases and that it enhanced GABAergic inhibition when applied to rat hippocampus slices. In vivo studies indicate that LGV depresses the spontaneous locomotor activity of mice. Its activity on a molar basis was some 300 times greater than that of gamma-vinyl-GABA.