Novel modulators of α-Synuclein / Synapsin-III interaction as potential antiparkinsonian agents

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder in the world today. Despite its growing impact on society, available therapies, which present some major drawbacks, are only capable of slowing down neuronal degeneration. For these reasons, developing novel therapeutic agents is now more important than ever. α-Synuclein (α-Syn) is the most studied presynaptic protein involved in the pathogenesis of PD and its misfolded forms are the main constituents of amyloid aggregates, strongly correlated with the disease. Synapsin-III (Syn-III) is a presynaptic protein with a crucial role in dopaminergic neurotransmission, as modulator of vesicle trafficking, fusion and binding. Recent results (5,6,7) suggested that the α-Syn/Syn-III interaction is essential in the misfolding processes and pointed out the potential neuroprotective effects of cocaine and methylphenidate in cell lines and animal models affected by PD. For these reasons, we focused on the design and synthesis of a class of compounds, which showed an interesting activity on the α-Synuclein/Synapsin-III interaction, resulting in putative neuroprotective effects. The aim of the present communication on these novel modulators is to summarize our results on: - target validation; - SAR, together with biological and computational data.