title: CNS delivery of L-dopa by a new hybrid glutathione-methionine peptidomimetic prodrug.
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.
authors.affiliation: Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100, Chieti, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Catia
authors.initials: C
authors.lastname: Cornacchia
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
authors.forename: Piera
authors.initials: P
authors.lastname: Sozio
authors.forename: Laura S
authors.initials: LS
authors.lastname: Cerasa
authors.forename: Antonio
authors.initials: A
authors.lastname: Iannitelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Fontana
authors.forename: Cinzia
authors.initials: C
authors.lastname: Nasuti
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D007980:Levodopa / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008715:Methionine / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D010455:Peptides; D011355:Prodrugs; D007980:Levodopa; D008715:Methionine; D005978:Glutathione