How do dopamine agonists work?

We look at the science behind medications that mimic the effect of dopamine in the brain — dopamine agonists.

When it comes to treating Parkinson’s, there are two main ways to address the lack of the chemical messenger dopamine. We can either replace the dopamine or mimic its effects. Sometimes both can be done at the same time by using different types of drugs alongside each other.

Levodopa based medications are the gold standard treatment for Parkinson’s. They work by replacing dopamine — nerve cells remaining in the brain can turn levodopa into dopamine. This type of medication is often combined with other drugs to help the levodopa reach the brain cells, and to make dopamine stick around longer. You can read more about how levodopa works, and why we can’t just take dopamine tablets, in this previous blog post.

An alternative mechanism is to mimic what the dopamine chemical messenger does in the brain. Drugs that act as dopamine agonists — such as apomorphine, ropinirole and pramipexole — do this by fooling brain cells into thinking they are dopamine.

A chemical message

There are many different types of chemical messengers used all over our bodies. For instance, insulin is used by the pancreas to encourage cells to take up sugar from the blood when sugar levels rise, while adrenaline is produced by the adrenal glands and acts to increase heart rate and get the body ready for the fight or flight response.

But signals don’t always involve a whole body response, individual cells communicate with each other by sending chemical messages as well. In fact, they do this all the time — sending out hundreds of different molecules that relay a host of information about the status of the cell and its environment.

The brain uses lots of chemical messengers to orchestrate complex communications that allow us to think, feel, move, remember and much more. Different signalling molecules are used by individual parts of the brain, allowing them to carry out their function. For example, dopamine is used by the substantia nigra to send messages to the parts of the brain that control movement.

How can you fool a brain cell?

On a whole body or single cell level, there are two components required for this type of message to work. Firstly a chemical messenger, and secondly a way to respond to it. Responding to a message means being able to pick up the signalling molecule using something called a receptor, which is found on the outside of the cell surface.

These receptors are designed to perfectly fit a certain type of molecule, and that’s where the mimicry can come into play. By designing a drug molecule that looks like a chemical messenger, we can activate the receptor.

Many different dopamine receptors

Dopamine signalling is a little more complex — there are at least 5 varieties of dopamine receptor that can respond to this messenger. The receptors are classified in two families:

• D1 and D5 are in the D1-like family
• D2, D3 and D4 are in the D2-like family

The reason for so many different receptors is so the brain can use the dopamine signal to activate different responses in different parts of the brain. For instance, in the D1-like family, the D5 receptor can be found in brain regions that play a role in emotion and behaviour, long-term memory and smell. In the D2-like family, the D2 receptor is most abundant in the basal ganglia —where it has a role in motor control and learning — while D3 receptors are found in various regions of the brain and are involved in encouraging rewarding behaviour.

Why is this important? Well it helps explain the main difference between the dopamine the brain produces and dopamine agonist. Natural dopamine will activate any of the dopamine receptors in the region of the brain where it is released, whereas dopamine agonists are unable to target specific locations but are able to be more selective and activate specific dopamine receptors.

When it comes to developing these types of medications, dopamine agonists with different activities have been used to treat a range of conditions from hypertension, to erectile dysfunction and Parkinson’s. But for Parkinson’s, the idea is that dopamine agonists can reach the regions of the brain, and work on the right type of receptors, to help the brain continue to control movement.

A short history of dopamine agonists

While levodopa has been on the scene since the 1960s, apomorphine was first proposed as a treatment for movement disorders 150 years ago. But it wasn’t until the 1950s that its potential for Parkinson’s was confirmed. While this drug was the first dopamine agonist to be used to treat Parkinson’s it has a number of problems. Apomorphine has a short duration of action, it needs to be injected and it can have some pretty ugly side effects, which left it sidelined and in pre-clinical research for the best part of 50 years. And it was only approved as a treatment for advanced Parkinson’s by the European Medical Association in 2006.

In the meantime, oral dopamine agonists had been developed and in the 1980s these were being used alongside levodopa as an adjunct therapy. These early dopamine agonists—including bromocriptine, cabergoline, and pergolide — were based on a chemical found in the ergot fungus and were able to mimic dopamine and interact with the D2 type receptors.

Unfortunately, these early dopamine agonists have side effects and, in some people, caused heart problems. Today ergot dopamine agonists are less commonly used. Instead tablet forms of dopamine agonists tend to be the newer, non-ergot dopamine agonists that became available from the late 1990s:

• Ropinirole is a selective dopamine D2-like receptor agonist and was the first available non-ergot dopamine agonist that could be taken as a tablet. While its beneficial effects in Parkinson’s comes from its action on the D2 receptor, it has stronger binding with the D3 receptor. The Requip branded form was approved in Europe in 1996. Other branded forms as well as generic, unbranded tablets are now available.
• Pramipexole also targets the D2-like receptors. The Sifrol branded form was approved by the EMA in 1997. Other branded forms as well as generic unbranded tablets are now available.

Developing better dopamine agonists

Advances in dopamine agonist medications in the 21st century have focused on the method of delivering these drugs. While apomorphine was sidelined for so long, one of the reasons clinical research of this non-ergot drug continued was the possibility that it could by-pass the need to swallow medications and can even be delivered continuously by a pump. This is a benefit for many people with advanced Parkinson’s who find oral medications no longer work or are too difficult to take.

But more controlled, or continuous delivery, and the need to take fewer drugs wouldn’t only benefit those in the later stages of the condition. That’s why different delivery mechanisms and formulations of dopamine agonists have been developed, such as the rotigotine transdermal skin patch (trade name Neupro), which was approved in 2006, and various once-a-day slow release tablets of pramipexol and ropinerol. You can find a list on the Parkinson’s UK website.

There are also ongoing pre-clinical studies and active clinical trials of other reformulated dopamine agonist medications, including:

• two phase 3 trials of an under the tongue apomorphine dissolvable strip (trial identifiers NCT02469090 and NCT02542696)
• a phase 1/2 trial of the 3 months ropinirole ProNeura™ implant (trial NCT03250117)
• pre-clinical studies of a transdermal form of apomorphine by research company 4P Therapeutics, which has recently been acquired by Nutriband Inc.
• positive results from a phase 3 study of a ropinirole patch

These developments could soon allow for additional options when it comes to treating Parkinson’s. And more choices allow for greater tailoring of medication regimes to meet the needs of individuals and better manage the symptoms of the condition.

Benefits of dopamine agonists

There is one final twist in the story about dopamine agonists. In the early 2000s, there was another feature of dopamine agonists under investigation — the possibility that they could help to protect brain cells. Unfortunately early suggestions of a protective effect of these drugs, which were highlighted in brain imaging studies, have yet to be substantiated. To date there are no treatments that have conclusively been demonstrated to slow the progression of Parkinson’s.

So, where do we stand with dopamine agonists? Dopamine agonists are currently used in clinical practice, sometimes alone, sometimes alongside other treatments. While these medications cause side effects such as dyskinesia less frequently than levodopa, even the newer dopamine agonists still cause a number side effects — these can include nausea and hallucinations — and they have been linked to sudden sleep attacks and increased risk of impulsive and compulsive behaviours. In fact, this latter side effect recently made the news as new research suggests that around half of people taking dopamine agonists may experience impulsive behaviours. You can read more about this in our blog post:

Do dopamine agonists cause impulsive behaviour?

When it comes to starting Parkinson’s medications…

The best comparative study suggests that there is not much to choose between the different classes of Parkinson’s medication in terms of symptom control and quality of life in the early stages. We still need better evidence on longer term effectiveness.

— Claire Bale, ‘Starting Parkinson’s drugs — research explained’.

With ongoing improvements in drug treatments for Parkinson’s, today we can manage symptoms better than ever before. But the drugs that are available are far from perfect, and we still need treatments that can slow the loss of precious brain cells as well as better ways to manage the non-motor symptoms of the condition.

Ultimately, it is through research that we will get new and better treatments. Through the tireless efforts of the many Parkinson’s researchers worldwide, alongside the guidance and support of the Parkinson’s community, we are making headway. But to ensure new treatments become a reality, we need everyone to get involved. From taking part in studies, to helping to shape research, there is a role and an opportunity for everyone affected by Parkinson’s. If you’re interested in finding out about these opportunities, or just want to stay connected with the latest research, the Research Support Network is for you.

You can find out more about Parkinson’s treatments and therapies, and their side effects, on the Parkinson’s UK website. If you have any concerns about your medication, or would like to discuss what treatments are best for you, please speak to your medical team. This blog is not meant as health advice. You should always consult a qualified health professional or specialist before making any changes to your medications or lifestyle.