Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Discontinued

Abstract

Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates. The development of new highly selective adenosine A2A receptor antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in patients with PD. To date, the clinical research regarding A2A antagonists and their potential utilization in PD therapy continues to evolve between drugs just or previously discontinued (preladenant and vipadenant), new derivatives in development (tozadenant, PBF-509, ST1535, ST4206 and V81444) and the relatively old drug istradefylline, which has finally been licensed as an anti-parkinsonian drug in Japan. All these compounds have been shown to have a good safety profile and be well tolerated. Moreover, results from phase II and III trials also demonstrate that A2A antagonists are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. In addition, early findings suggest that A2A antagonists might also be efficacious as monotherapy in patients at an early stage of PD. This review summarizes pharmacological and clinical data available on istradefylline, tozadenant, PBF-509, ST1535, ST4206, V81444, preladenant and vipadenant.

Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson’s disease

“…Surprisingly, the addition of either an A 2A receptor antagonist or of an NR2B receptor antagonist alone did not increase and/or prolong the effect of L-Dopa on the level of contralateral rotation. These observations contrast with literature reports [34,37,65] but may reflect the fact that lower doses of A 2A and NR2B antagonists were used in our study. Despite the lack of efficacy when the compounds were administered alone with L-Dopa, the combined administration of an A 2A and a NR2B receptor antagonist to the same dose of L-DOPA significantly increased the magnitude of the L-Dopa effect on the level of contralateral rotations.…”

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

“…The opposite pharmacological profile was obtained with KW 6002, which produced strong locomotor activation at doses that were ineffective at blocking glutamate release from cortical afferents in the striatum [32]. KW 6002 is thus a promising anti-parkinsonian agent and is already being successfully used for the treatment of Parkinson's disease [33][34][35].…”

Parkinson’s Disease: Insights from Drosophila Model

“…Taking advantage of studies from animal models such as drosophila certain pharmacotherapies and non-pharmacotherapies have been developed which are in different stages in clinical trials to validate their efficacy, safety, and tolerability. Pharmacotherapies include adenosine A2A receptor antagonists [196], glutamate AMPA receptor antagonists [197], monoamine oxidase inhibitors [198], anti-apoptotic agents [199], and antioxidants [200]. Non-pharmacotherapies also offer alternative approaches for treatment of the disease which include the use of viral vector gene therapy [201], stem cell transplants [202], and microRNAs [203].…”