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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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.