Synthesis and study of L-dopa-glutathione codrugs as new anti-parkinson agents with free radical scavenging properties

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.