title: Synthesis and study of L-dopa-glutathione codrugs as new anti-Parkinson agents with free radical scavenging properties.
abstract: A series of novel molecular combinations (1-4), in which L-dopa (LD) is linked covalently via an amide bond with glutathione (GSH), were synthesized and evaluated as potential anti-Parkinson agents with antioxidant properties. These conjugates were characterized by evaluating solubility, chemical and enzymatic stabilities, and apparent partition coefficient (log P). Derivatives 2 and 4 were tested for their radical scavenging activities, by use of a test involving the Fe(II)/H2O2-induced degradation of deoxyribose. In this study, the antioxidant efficacy of codrugs 1 and 3 was also assessed through the evaluation of plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Furthermore, the central nervous effects and rat striatal concentration of LD and dopamine (DA) have been evaluated after oral administration of codrugs 1 and 3. Tested compounds prolonged the plasma LD levels and were able to induce sustained delivery of DA in rat striatum with respect to an equimolar dose of LD. The results suggest that compounds 1 and 3 could represent useful new anti-Parkinson agents devoid of the pro-oxidant effects associated with LD therapy and potentially able to restore the GSH depletion evidenced in the substantia nigra pars compacta (SNpc) of PD patients.
authors: Dipartimento di Scienze del Farmaco, Università G. D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy.
authors: Francesco
authors: F
authors: Pinnen
authors: Ivana
authors: I
authors: Cacciatore
authors: Catia
authors: C
authors: Cornacchia
authors: Piera
authors: P
authors: Sozio
authors: Antonio
authors: A
authors: Iannitelli
authors: Mara
authors: M
authors: Costa
authors: Laura
authors: L
authors: Pecci
authors: Cinzia
authors: C
authors: Nasuti
authors: Franco
authors: F
authors: Cantalamessa
authors: Antonio
authors: A
authors: Di Stefano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007980:Levodopa / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D016166:Free Radical Scavengers; D007980:Levodopa; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione; D004298:Dopamine