A small molecule reduces both parkinsonism and l-dopa-induced dyskinesia in animal models of Parkinson's disease.

Abstract

Maximizing clinical benefits of therapeutics while minimizing adverse effects is a central challenge in drug development. For Parkinson's disease (PD), l-3,4-dihydroxyphenylalanine (l-dopa) is the most effective treatment available, but chronic use is associated with periods of reduced efficacy (motor fluctuations) and the debilitating on-target side effect of l-dopa-induced dyskinesia. To disentangle the molecular mechanisms underlying l-dopa's antiparkinsonian effects versus its dyskinetic effects, we analyzed transcriptomic data from the striata of mice exposed to different l-dopa doses, identifying distinct gene expression signatures associated with l-dopa's effect on parkinsonian motor symptoms and dyskinesia. By comparing these gene expression signatures with a large dataset of in vitro gene expression profiles of drug perturbations, we identified SB-0107, a positive allosteric modulator of protein kinase A type II with previous clinical experience that boosts l-dopa's benefits while reducing dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque model of PD. Deuterated analogs, including SB-0110, were developed that improved both pharmacokinetics and pharmacological effects. This dual effect, established safety profile of the parent compound, and improved properties of the deuterated analog support further development of this compound as an adjunct treatment to l-dopa therapy for PD.