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

J Med Chem. 1986 May;29(5):687-91. doi: 10.1021/jm00155a018.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Brain / metabolism
  • Dopamine / blood
  • Haplorhini
  • Hydrolysis
  • Kinetics
  • Levodopa / administration & dosage*
  • Levodopa / blood
  • Lymph / metabolism
  • Male
  • Mice
  • Oxotremorine / pharmacology
  • Phenylpropionates / metabolism*
  • Rats
  • Reserpine / pharmacology
  • Time Factors

Substances

  • Phenylpropionates
  • 1,3-dihexadecanoyl-2-(2-amino-3-(3,4-dihydroxyphenyl)propanoyl)propane-1,2,3-triol
  • Levodopa
  • Oxotremorine
  • Reserpine
  • Dopamine