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

Abstract

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.

Prodrugs and Drug Delivery Systems

“…25 Another related approach for anticonvulsant drug design was the synthesis of a glyceryl lipid (8.18, R = linolenoyl) containing one GABA molecule and one vigabatrin molecule, a mechanism-based inactivator of GABA amino-transferase and anticonvulsant drug (see Section V,C,3,a of Chapter 5). 26 This compound inactivates GABA aminotransferase in vitro only if brain esterases are added to cleave the vigabatrin from the glyceryl lipid. It also is 300 times more potent than vigabatrin, in vivo, presumably because of its increased ability to enter the brain.…”

The 2011 E. B. Hershberg Award for Important Discoveries in Medicinally Active Substances: (1S,3S)-3-Amino-4-difluoromethylenyl-1-cyclopentanoic Acid (CPP-115), a GABA Aminotransferase Inactivator and New Treatment for Drug Addiction and Infantile Spasms

“…17 Several approaches have been taken to increase the brain concentrations of GABA. One approach has been to make prodrugs of GABA, 18,19 but except for progabide, this has not been highly successful. Another approach taken to increase brain GABA levels is the use of a compound that crosses the blood-brain barrier and then inhibits or inactivates GABA-AT, the enzyme that degrades GABA.…”

Biological Properties of Schiff Bases and Azo Derivatives of Phenols

“…It is considered to act as a natural calming and anti-epileptic agent in the brain. Since GABA is not transported efficiently into the brain from the bloodstream, most GABA found in the brain is manufactured there [184][185][186][187][188][189][190][191][192][193][194][195].…”

“…(Scheme 20) [195][196]. Fengabine (239) is also a Schiff base and acts as an [121,168] 216 [121,168] 217 [121,168] 222 [163] 223 [163] 218 [163] 224 [163] 225 [163] 219 [163] O O S NH [197][198][199][200].…”