gamma-Aminobutyric acid esters. 3. Synthesis, brain uptake, and pharmacological properties of C-18 glyceryl lipid esters of GABA with varying degree of unsaturation.
A series of 14C-labeled and unlabeled di-gamma-aminobutyric acid esters of glyceryl lipids having zero to three double bonds (stearoyl, oleoyl, linoleoyl, and linolenoyl) were synthesized. Measurements of the octanol/water partition coefficients of the compounds showed an increase with decreasing number of double bonds (i.e., from linolenoyl to stearoyl). The brain-uptake index went up from 31.5 (linolenoyl) to 45.1 (stearoyl) and similarly the brain-penetration index went up from 15 (linolenoyl) to 28 (stearoyl). Intraperitoneal injections of these di-GABA lipid esters produced a substantial inhibition of the general motor activity in mice at a dose of 30 mg/kg; the most active molecules were those containing two and three double bonds, i.e., the linolenoyl and linolenoyl derivatives. This is in reverse order to that predicted by brain-uptake and lipid-solubility properties, suggesting that the structure of the fatty acid side chain may be an additional factor in influencing biological activity.
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D005680:gamma-Aminobutyric Acid