Maleic- and fumaric-diamides of (O,O-diacetyl)-L-Dopa-methylester as anti-Parkinson prodrugs in liposomal formulation

J Drug Target. 2006 Nov;14(9):652-61. doi: 10.1080/10611860600916636.

Abstract

The maleic and fumaric diamides preparation of (O,O-diacetyl)-L-Dopa-methylester [(+)-4, (+)-5] are reported; they were synthesized in order to attenuate marked fluctuations of L-DOPA (LD) plasma levels and to overcome the problem of low bioavailability of LD. The new compounds were characterized evaluating solubility, chemical stability, apparent partition coefficient (log P) and comparing neostriatum dopamine (DA) levels in freely moving rats after i.p. administration of prodrugs [(+)-4, (+)-5] with prodrugs in liposomal formulations [(+)-4Lip, (+)-5Lip]. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of LD in human plasma was observed. Among the studied products, prodrug was able to induce sustained delivery of DA in rat striatal dialysate with respect to equimolar i.p admistration of LD. Furthermore, neostriatum DA concentration after administration of the synthesized prodrugs vs. prodrugs in liposomal formulations was compared (+)-4Lip, (+)-5Lip). The results suggest that cis dimeric prodrug (+)-4 and (+)-4Lip can improve the release of DA in rat brain and demonstrate the potential of these formulations for controlled delivery of antiparkinson agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / administration & dosage
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Antiparkinson Agents / administration & dosage*
  • Antiparkinson Agents / chemical synthesis
  • Antiparkinson Agents / pharmacokinetics*
  • Calibration
  • Chemistry, Pharmaceutical
  • Chromatography, High Pressure Liquid
  • Dopamine / metabolism
  • Drug Compounding
  • Drug Stability
  • Electrochemistry
  • Fumarates / chemistry*
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Indicators and Reagents
  • Levodopa / administration & dosage
  • Levodopa / analogs & derivatives*
  • Levodopa / chemistry
  • Levodopa / pharmacology
  • Liposomes
  • Male
  • Maleates / chemistry*
  • Mass Spectrometry
  • Microdialysis
  • Particle Size
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • (O,O-diacetyl)-L-Dopa-methylester fumaric diamide
  • (O,O-diacetyl)-L-Dopa-methylester maleic diamide
  • Amides
  • Antiparkinson Agents
  • Fumarates
  • Indicators and Reagents
  • Liposomes
  • Maleates
  • Prodrugs
  • Levodopa
  • Dopamine