What's Hot in PD? A2A Receptor Antagonists and Parkinson’s Disease Treatment

One of the exciting recent changes in the treatment approach to Parkinson’s disease has been the development of new brain targets that have attempted to move the field beyond the typical dopamine and dopamine agonist-based treatments. One of the brain targets that has gleaned tremendous interest from multiple pharmaceutical companies, as well as from leading scientists from around the world, has been the adenosine A2 receptor. In this month’s What’s Hot column, I will review what is known about this brain receptor, and also provide an update on the status of clinical trials focused on the A2A receptor antagonists for treatment of Parkinson’s disease.

What is the adenosine A2A receptor? There is a group of circuits in the brain called the basal ganglia that are collectively involved in the underlying problems that result in the symptoms of Parkinson’s disease. The basal ganglia have a ton of adenosine A2A receptors located on the outside of nerve cells that are referred to as neurons. Many of these receptors have been observed to be co-located next to dopamine receptors. Scientists believe that you can either activate the dopamine receptor, or alternatively block the adenosine A2 receptor as a means to improving the symptoms of Parkinson’s disease. There has been some speculation that this class of drugs may when used in combination with dopaminergic drugs (e.g. levodopa and agonists) facilitate a reduction in the dosage of dopamine, and a coincident reduction in side effects.

Istradefylline is an adenosine A2A receptor antagonist that has been tried in multiple human studies of patients suffering with Parkinson’s disease. The results of these studies revealed a mild beneficial effect on wearing off and on motor fluctuations. Istradefylline did not achieve FDA approval in the United States, but has been approved for use in Japan. Biotie has been investigating another A2A receptor antagonist for Parkinson’s disease, tozadenant (SYN115). Early treatment results have revealed improvements in “off” time. Finally, Merck recently investigated another drug named Preladenant. Preladenant is also adenosine A2A receptor antagonist. Early studies revealed promising effects for this compound on PD related “off” periods. Unfortunately, three separate phase III trials did not provide evidence for efficacy over a placebo pill. Vipadenant (BIIB014) and ST-1535 are two A2A receptor compounds that remain under investigation in animal models for Parkinson’s and other diseases. Here I listed other compounds known to block the adenosine A2A receptor, and have been used in various animal and human studies: ATL-444, MSX-3, SCH-58261, 412, 348, 442,416, VER-6623, 6947, 7835, ZM-241,385.

An important point for patients to keep in mind is that the A2A receptor may be affected by the intake of certain foods or drinks. We reported in a previous edition of the What’s Hot Column on recent “animal experiments that have, like in human trials and epidemiological studies, revealed a potential caffeine benefit for Parkinson’s disease sufferers. The benefit is believed to be underpinned by caffeine’s action in blocking the adenosine A2A brain receptor. In humans there have been several small studies and also anecdotal observations that support the idea that there is a mild to moderate caffeine benefit in Parkinson’s.”

It is exciting that pharmaceutical companies and scientists are beginning to look beyond the dopaminergic system for better therapies to treat those suffering from Parkinson’s disease. We should not get too disappointed in the early drug trial failures, as we are just beginning to explore novel and potentially therapeutic areas of the brain that may help this and the next generation of Parkinson’s patients achieve treatment success.

Selected References

Hickey P, Stacy M. Adenosine A2A antagonists in Parkinson's disease: what's next? Curr Neurol Neurosci Rep. 2012 Aug;12(4):376-85. doi:10.1007/s11910-012-0279-2. Review.

Federico S, Spalluto G. Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands. Expert Opin Ther Pat. 2012 Apr;22(4):369-90. doi: 10.1517/13543776.2012.669375. Epub 2012 Mar 22. Review.

Kulisevsky J, Poyurovsky M. Adenosine A2A-receptor antagonism and pathophysiology of Parkinson's disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. doi: 10.1159/000331768. Epub 2011 Nov 30. Review.

Armentero MT, Pinna A, Ferré S, Lanciego JL, Müller CE, Franco R. Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease. Pharmacol Ther. 2011 Dec;132(3):280-99. doi:10.1016/j.pharmthera.2011.07.004. Epub 2011 Jul 23. Review.

 

You can find out more about our National Medical Director, Dr. Michael S. Okun, by also visiting the Center of Excellence, University of Florida Health Center for Movement Disorders and Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life and 10 Breakthrough Therapies for Parkinson's Disease.

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