Glycosyl derivatives of dopamine and L-dopa as anti-Parkinson prodrugs: synthesis, pharmacological activity and in vitro stability studies

J Drug Target. 2003 Jan;11(1):25-36. doi: 10.1080/1061186031000086090.

Abstract

Novel glycosyl derivatives of dopamine and L-dopa (I-IV) are synthesized in order to overcome the problem of blood-brain barrier low permeability of dopamine and of low bioavailability of its precursor L-dopa. Esters synthesized link dopamine and L-dopa, by a succinyl linker, to C-3 position of glucose (I and II) and to C-6 of galactose (II and IV). The chemical and enzymatic stabilities of esters synthesized were evaluated in order to determine both their stability in aqueous medium and their feasibility in undergoing enzymatic cleavage by rat plasma to regenerate the original drug. Furthermore, we have shown the central effects of esters I-IV on classic dopaminergic models, such as morphine induced locomotion and reserpine-induced hypolocomotion. From the result obtained compounds I-IV appeared moderately stable in a pH 7.4 buffered solution and in rat plasma. Furthermore, pharmacological studies showed that both dopamine derivatives (I and II) were equiactive in reversing reserpine-induced hypolocomotion in rats, and both were more active than L-dopa or ester III and IV, while II and III were more potent in reducing morphine-induced locomotion than I and IV. The minimal vascular effects of these derivatives allow us to underline the possibility to use them in pathologies, such as Parkinson disease, characterised by an evident decreasing of dopamine concentration in the brain.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antiparkinson Agents / chemical synthesis
  • Antiparkinson Agents / pharmacology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology
  • Dopamine / analogs & derivatives
  • Dopamine / chemical synthesis
  • Dopamine / pharmacology*
  • Drug Stability
  • Galactose / analogs & derivatives
  • Galactose / chemical synthesis
  • Galactose / pharmacology
  • Glucose / analogs & derivatives
  • Glucose / chemical synthesis
  • Glucose / pharmacology
  • Levodopa / analogs & derivatives
  • Levodopa / chemical synthesis
  • Levodopa / pharmacology*
  • Male
  • Mice
  • Motor Activity / drug effects*
  • Motor Activity / physiology
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Rats
  • Rats, Wistar

Substances

  • Antiparkinson Agents
  • Prodrugs
  • Levodopa
  • Glucose
  • Dopamine
  • Galactose