A2A Receptor Antagonists and Parkinson’s Disease Treatment

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration.

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:

1. 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.

2. 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.

3. 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.

4. 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.

Posted: 6/4/2013 10:03:57 AM by Cathy Whitlock

Browse current and archived What's Hot in PD? articles, the National Parkinson Foundation's monthly blog for people with Parkinson's written by our National Medical Director, Dr. Michael S. Okun. 

June 2015
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May 2015
Leaps in Deep Brain Stimulation Technology

April 2015
What to tell Parkinson’s patients about diet and taking statin drugs

March 2015
Everything a Parkinson’s Disease Patient Needs to Know About the New Dopamine Pump

February 2015
Tips for Parkinson’s Disease Patients Switching from Sinemet or Madopar to Rytary (IPX066)

January 2015
More Evidence Linking Gut Bacteria to Parkinson’s Disease: A Guide for Patients

December 2014
Two New Therapies for Parkinson’s Disease Patients to get Excited About: Vaccines and Monoclonal Antibodies

November 2014
The Importance of a Monitoring Strategy When Prescribing Dopamine Agonists: Lessons from the National Parkinson Foundation Data

October 2014
Is Midlife Migraine Related to Late Life Parkinson’s Disease?

September 2014
Deep Brain Stimulation for Parkinson’s Disease: NPF Congratulates Mahlon DeLong and Alim-Louis Benabid and Looks to a Bright Future in Human Neural-Network Modulation

August 2014
Everything You Need to Know About Medical Marijuana and Parkinson’s Disease

July 2014
The End for Levodopa Phobia: New Study Shows Sinemet is a Safe Initial Therapy for Treatment of Parkinson's Disease

June 2014
Is light therapy a potential treatment modality in Parkinson’s disease?

May 2014
How does the most common genetic cause of Parkinson’s Disease (LRRK2) cause Parkinson’s disease and could it be used to help develop a better therapy?

April 2014
An Update on DAT Scanning for Parkinson’s Disease Diagnosis

March 2014
Could Northera (Droxidopa) Be an Alternative Treatment for Low Blood Pressure and Passing Out Symptoms?

February 2014
The Dream of a Pill Free Existence and the Continuous Dopaminergic Pump for the Treatment of Parkinson's Disease

January 2014
Should I take Inosine to Raise my Uric Acid Levels and Treat my Parkinson’s Disease?

December 2013
Could Fungus and Mold be an Important Contributor to Parkinson’s Disease?

November 2013
Pimavanserin and the Hope for a Better Drug for Hallucinations and Psychosis in Parkinson’s Disease

October 2013
Halting of the Creatine Study

September 2013
The Importance of Identifying and Treating Caregiver Strain

August 2013
Putting Parkinson’s Disease Information into the Palm of Your Hand: Parkinson’s Enters the Smartphon

July 2013
What Parkinson’s Disease Patients Need to Know about H. Pylori Gastrointestinal Infections

June 2013
A2A Receptor Antagonists and Parkinson’s Disease Treatment

May 2013
Another Setback for Trophic Factor Treatment in Parkinson's Disease

April 2013
IPX066 and What Patients Really Want in New Carbidopa/Levodopa (Sinemet) Formulations

March 2013
The Weather Forecast for Parkinson’s Disease Calls for Worldwide Economic Storm

February 2013
Defeating the Barriers to Implementing Exercise Regimens in Parkinson’s Disease Patients

January 2013
When should you start medication therapy for Parkinson’s disease?

December 2012
Neurologist Care Reduces Hospitalizations in Parkinson's Disease

November 2012
A Victory in Court for Parkinson's Disease Patients who Require Ongoing Rehabilitative Therapies

October 2012
Given the recent FDA announcement about Mirapex (pramipexole), should I be worried about dopamine agonists?

September 2012
What about the new Parkinson’s Disease Vaccine? What should I know?

August 2012
Caffeine as a Potential Treatment for Parkinson’s Disease

July 2012
Time to Consider GPi DBS for Parkinson’s Disease: A Shift in the Practice of Patient Selection for DBS

June 2012
A New Treatment for Parkinson’s Disease-Related Constipation

May 2012
Too Many Pills: Improving Delivery Systems for Parkinson’s Disease Drugs

April 2012
Measuring Quality and Assessing Depression in Parkinson's Disease

March 2012
Watch out for Unexpected Obstacles if You Use a Cueing Strategy to Break Freezing of Gait in Parkinson’s Disease

February 2012
Pill Color, Generic Medications and Insurance Issues: Important Medication-Related Tips for the Parkinson’s Disease Patient

January 2012
Are Blood Tests for Parkinson’s Disease on the Horizon?

December 2011
Placing Stem Cells in Animal Models of Parkinson’s Disease: Another Important Step

November 2011
Important News for the Parkinson’s Disease Community: More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression

October 2011
The Case for All Parkinson’s Disease Patients to be Co-managed by a Primary Care-Neurologist Team

September 2011
Scientists say Research on Brain Proteins Involved in Parkinson’s Disease is “Shaping” Up

August 2011
Who Actually Takes Care of Most of the Parkinson’s Patients Worldwide: The Need for Education and the Parkinson’s Toolkit

July 2011
If you are Dizzy or Passing Out, it could be Your Parkinson’s Disease or Parkinson’s Disease Medications

June 2011
How Will Group Visits for Parkinson’s Disease Fit into the Future of Parkinson’s Disease Care?

May 2011
Why Patients Should be Wary of Chelation Therapy for Parkinson’s Disease

April 2011
Opening the Door to Gene Therapy in Parkinson’s Disease: The Need for Refinement of the Technology and Approach

March 2011
Does it Matter if I Can’t Get Brand Sinemet?

February 2011
Should I get a DaTscan or PET scan to confirm my diagnosis of Parkinson’s disease?

January 2011
A Critical Reappraisal of the Worst Drugs in Parkinson’s Disease

December 2010
Environmental Risks for PD: Manganese, Welding, Mining, and Parkinsonism

November 2010
Calling for the FDA to Revise the Eight Sinemet a Day Rule

October 2010
Dry Cleaning Solvents and Potential Environmental Risks for Developing Parkinson’s Disease

September 2010
Maintaining the Balance: Why Parkinson’s Disease Patients Need to Understand Drug Recalls, Withdrawals, and Safety Alerts

August 2010
Shining a Light on Parkinson’s Disease: Optogenetics Has a Bright Future in Research

July 2010
Poor Medication Management of Parkinson's Disease During Hospital Admissions: Patients and Families Can Improve Their Hospital-Based Management

June 2010
Why Are Patches and Continuous Release Technology a Big Deal to Parkinson's?

May 2010
Is the PD SURG Trial Another Surge Forward for DBS Therapy?

April 2010
Cycling in PD in Those Who Can’t Walk: Is it Possible?

March 2010
New iPS Stem Cells for PD: What Does it Mean?

February 2010
Time for Comprehensive Care Networks for PD

January 2010
Is Parkinson's Disease a Prion Disease?

December 2009
Parkinson's Disease Linked to Gaucher's Disease

November 2009
Brain Cells Keep Time Stamps: Implications for Parkinson's Disease Therapies

October 2009
Is it Safe to Have an MRI with a DBS in Place?

September 2009
Take Care of Your Bones as They Are Affected in Parkinson's Disease (Even in Men)

August 2009
Is it Time to Start Paying Attention to Pain Symptoms in Parkinson's Disease Patients?

July 2009
Glutathione Fails to Demonstrate Significant Improvement in PD Symptoms

June 2009
Keeping an Eye on Trials Important to the Parkinson's Disease Patient

May 2009
Increased Risk of Melanoma in Parkinson's Disease

April 2009
Finally a DBS Expert Consensus Statement Aimed at Their True Customers: The Patients

March 2009
Pesticides and Environmental Exposure in Parkinson's disease: Should We Stay Away From the Stink Truck?

February 2009
Is Exercise Effective Treatment and Protection Against PD?

January 2009
Why are Transplant Trials Struggling to Succeed in the Treatment of PD?

December 2008
Are Monoamine Oxidase Inhibitors Disease Modifying or Neuroprotective in PD?

November 2008
Update on Gene Therapy for Parkinson's Disease

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Each month, we will feature a new column by NPF's National Medical Director, Dr. Michael Okun, on the latest developments in Parkinson's disease research. Read the latest "What's Hot in PD?" below.

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