Original Article

Amino Acids

, Volume 42, Issue 1, pp 261-269

First online:

CNS delivery of l-dopa by a new hybrid glutathione–methionine peptidomimetic prodrug

  • Francesco PinnenAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Ivana CacciatoreAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Catia CornacchiaAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Adriano MollicaAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Piera SozioAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Laura S. CerasaAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Antonio IannitelliAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Antonella FontanaAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio”
  • , Cinzia NasutiAffiliated withDipartimento di Medicina Sperimentale e Sanità Pubblica, Università di Camerino
    • , Antonio Di StefanoAffiliated withDipartimento di Scienze del Farmaco, Università “G. D’Annunzio” Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder associated primarily with loss of dopamine (DA) neurons in the nigrostriatal system. With the aim of increasing the bioavailability of l-dopa (LD) after oral administration and of overcoming the pro-oxidant effect associated with LD therapy, we designed a peptidomimetic LD prodrug (1) able to release the active agent by enzyme catalyzed hydrolysis. The physicochemical properties, as well as the chemical and enzymatic stabilities of the new compound, were evaluated in order to check both its stability in aqueous medium and its sensitivity towards enzymatic cleavage, providing the parent LD drug, in rat and human plasma. The radical scavenging activities of prodrug 1 was tested by using both the DPPH–HPLC and the DMSO competition methods. The results indicate that the replacement of cysteine GSH portion by methionine confers resistance to oxidative degradation in gastric fluid. Prodrug 1 demonstrated to induce sustained delivery of DA in rat striatal tissue with respect to equimolar LD dosages. These results are of significance for prospective therapeutic application of prodrug 1 in pathological events associated with free radical damage and decreasing DA concentration in the brain.

Keywords

l-Dopa Glutathione Methionine Parkinson’s disease