Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease

Treatment of motor fluctuations in Parkinson's disease (PD) remains an unmet challenge. Adenosine 2A (A_2A) receptors are located along the indirect pathway and represent a potential target to enhance l-3,4-dihydroxyphenylalanine (l-DOPA) antiparkinsonian action.

This article summarizes the preclinical and clinical literature on A_2A antagonists in PD, with a specific focus on their effect on off time, on time, and dyskinesia.

Several A_2A receptor antagonists have been tested in preclinical studies and clinical trials. In preclinical studies, A_2A antagonists enhanced l-DOPA antiparkinsonian action without exacerbating dyskinesia, but A_2A antagonists were generally administered in combination with a subthreshold dose of l-DOPA, which is different to the paradigms used in clinical trials, where A_2A antagonists were usually added to an optimal antiparkinsonian regimen. In clinical settings, A_2A antagonists generally reduced duration of off time, by as much as 25% in some studies. The effect of on time duration is less clear, and in a few studies an exacerbation of dyskinesia was reported. Two A_2A antagonists have been tested in phase III settings: istradefylline and preladenant. Istradefylline was effective in two phase III trials, but ineffective in another; the drug has been commercially available in Japan since 2013. In contrast, preladenant was ineffective in a phase III trial and the drug was discontinued. A phase III study with tozadenant will begin in 2015; the drug was effective at reducing off time in a phase IIb study. Other A_2A antagonists are in development at the preclinical and early clinical levels.