A lymphotropic prodrug of L-dopa: synthesis, pharmacological properties, and pharmacokinetic behavior of 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)prop anoyl] propane-1,2,3-triol.
A glyceride derivative of L-Dopa, 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propan oyl] propane-1,2,3-triol (1), was synthesized and tested as an orally administrable prodrug endowed with lymphotropic properties. In the oxotremorine and reserpine tests, 1 exhibited an anti-Parkinsonian activity of longer duration than L-Dopa. The time course of concentration of 1 in the intestinal lymph of rat was determined and compared to that of L-Dopa. The results clearly demonstrate that 1 is selectively absorbed from the intestinal tract by the lymphatic route without any chemical or enzymatic degradation. In the blood of rats and mice, 1 functions as a prodrug to release L-Dopa by hydrolysis. In comparison with L-Dopa itself, higher L-Dopa levels for a longer period of time were observed as well as much more favorable L-Dopa/dopamine ratios. Ultimately, studies using mice show that the administration of 1 brings about a prolonged increase of L-Dopa and dopamine levels in the brain, without initial transient peak in concentration observed after an equimolecular dose of L-Dopa.
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000097:blood; D000882:Haplorhini; D006868:Hydrolysis; D007700:Kinetics; D007980:Levodopa / Q000008:administration & dosage* / Q000097:blood; D008196:Lymph / Q000378:metabolism; D008297:Male; D051379:Mice; D010095:Oxotremorine / Q000494:pharmacology; D010666:Phenylpropionates / Q000378:metabolism*; D051381:Rats; D012110:Reserpine / Q000494:pharmacology; D013997:Time Factors
D010666:Phenylpropionates; C048805:1,3-dihexadecanoyl-2-(2-amino-3-(3,4-dihydroxyphenyl)propanoyl)propane-1,2,3-triol; D007980:Levodopa; D010095:Oxotremorine; D012110:Reserpine; D004298:Dopamine