Chemical Biology Approaches to Combat Parkinson’s Disease

Parkinson's disease (PD) is a debilitating neurodegenerative disease of the central nervous system characterized by loss of striatal dopaminergic projections from the substantia nigra. Although there is no known cure for PD, dopamine (DA) replacement using L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common therapy used to manage PD symptoms. L-DOPA is poorly absorbed into the brain and metabolized in the periphery causing its efficacy to wane with time. Additionally, within five years of use, L-DOPA can induce its own severe motor dysfunction, including dyskinesias, which can be irreversible. This underscores the need for the discovery and development of improved anti-parkinsonian therapeutics. We have identified a class of conformationally-constrained phenylethylamines based on a tranylcypromine scaffold and demonstrated that many compounds in this structural class exhibited partial or full relief of akinesia in a DA-deficient/DA transporter knockout (DAT-KO) mouse model of PD developed in the Caron laboratory. Two highly active arylcyclopropylamines from studies in DAT-KO mice were subsequently evaluated in a 6-hydroxydopamine-lesioned rat model to confirm their anti-parkinsonian and anti-dyskinesia activities. In these rats, both compounds improved lesioned-induced motor deficits that emulate akinesia. Target identification and activity assays suggest 5-HT2B and 2A as candidate targets to begin elucidation of novel non-dopaminergic pathways to combat PD.