Parkinson's Disease: Recent Updates in the Identification of Human Dopa Decarboxylase Inhibitors

Backround: Parkinson's disease is a pathology involving the progressive degeneration of dopaminergic neurons in the substantia nigra of the brain. L-DOPA combined with an inhibitor of DOPA decarboxylase, a pyridoxal 5'-phosphate-dependent enzyme, is still the most effective treatment for symptoms of Parkinson's disease. LDOPA increases synaptic dopamine, while the inhibitor of peripheral DOPA decarboxylase reduces the conversion of L-DOPA to dopamine in the systemic circulation, allowing for greater L-DOPA distribution into the central nervous system. CarbiDOPA and benserazide are the inhibitors currently used in Parkinson's disease treatment. However, carbiDOPA and trihydroxybenzylhydrazine, the active metabolite of benserazide, are substrate analogues both endowed with a hydrazine function, which irreversibly bind not only to DDC but also to free pyridoxal 5'-phosphate and pyridoxal 5'-phosphate-dependent enzymes. Therefore, the lack of DOPA decarboxylase specificity, responsible for various side effects and adverse reactions, is a negative factor in such treatment of the disease.

Aim of this review is to report on the most recent investigations regarding new DOPA decarboxylase inhibitors that could represent the starting point for possible Parkinson's disease drugs development. We focused on the common chemical features among all the identified inhibitors in order to seek shared structural motifs that could be involved in inhibition. Then, we highlighted the extent of inhibition, measured by means of in vitro and/or cell-based assays. Finally, we pointed out the state of the art in the metabolism of such classes of compounds, and discussed the possible advances in Parkinson's disease pharmacological treatment.