A series of multifunctional codrugs (1-4), obtained by joining L-Dopa (LD) and dopamine (DA) with
(R)-R-lipoic acid (LA), was synthesized and evaluated as potential codrugs with antioxidant and iron-chelating
properties. These multifunctional molecules were synthesized to overcome the pro-oxidant effect associated
with LD therapy. The physicochemical properties, together with the chemical and enzymatic stabilities of
synthesized compounds, were evaluated in order to determine both their stability in aqueous medium and
their sensitivity in undergoing enzymatic cleavage by rat and human plasma to regenerate the original drugs.
The new compounds were tested for their radical scavenging activities, using a test involving the Fe (II)-
H2O2-induced degradation of deoxyribose, and to evaluate peripheral markers of oxidative stress such as
plasmatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the plasma.
Furthermore, we showed the central effects of compounds 1 and 2 on spontaneous locomotor activity of
rats in comparison with LD-treated animals. From the results obtained, compounds 1-4 appeared stable at
a pH of 1.3 and in 7.4 buffered solution; in 80% human plasma they were turned into DA and LD. Codrugs
1-4 possess good lipophilicity (log P > 2 for all tested compounds). Compounds 1 and 2 seem to protect
partially against the oxidative stress deriving from auto-oxidation and MAO-mediated metabolism of DA.
This evidence, together with the “in vivo” dopaminergic activity and a sustained release of the parent drug
in human plasma, allowed us to point out the potential advantages of using 1 and 2 rather than LD in
treating pathologies such as Parkinson’s disease, characterized by an evident decrease of DA concentration
in the brain
