The Changing Landscapes of Parkinson’s Disease Medication.

 by Harry Cooper

Parkinson’s disease is the second most prevalent age-related degenerative brain illness (behind Alzheimer’s), estimated to affect ~1% of those over-60 globally. It is caused by the loss of dopamine producing neurons, resulting in widespread neuron death and manifesting as involuntary tremors due to a lack of dopamine in the body. Many other symptoms such as depression, insomnia, and gait disturbance have also been recorded. 

Naturally, there has been a search for chemicals that can mitigate the symptoms of this chronic illness and provide strong neuroprotection (the ability to protect neurons from degeneration and facilitate their recovery), which has had limited success as of 2024. The drugs in the current treatment landscape have been developed to help alleviate motor symptoms by enhancing dopaminergic transmission, with the clinically approved drugs developed so far falling under 5 main categories*.

The first is levodopa, commonly known as ʟ-DOPA, marketed as Sinemet or Madopar, that acts as a precursor to dopamine. Its structure allows it to cross the blood-brain barrier, where enzymes in the brain can subsequently convert it into dopamine. This is done within terminals throughout the brain’s striatal regions (areas that contain dopamine producing cells). It usually produces very promising results when taken, alleviating stiffness and slowness of movement. Unfortunately however, the positive effects only last for a limited time, after which the drug can instead give rise to dyskinesia - involuntary jerking movements. This can have detrimental effects on the lives of patients, exacerbating current symptoms further. This is due to ʟ-DOPA triggering extensive changes in DNA methylation - a common process in the body where cells change their levels of gene activity in response to environmental factors. The process involves enzymes placing molecular tags on specific genes in the form of methyl groups making them either more or less active. The research, published in the Journal of Neuroscience, found that after a prolonged dosage, nerve cells in the striatum of the patient could lose certain methyl ‘tags’ with other areas becoming overly methylated. This leads to the nerve cells not functioning correctly in turn causing dyskinesia. And so most treatment cycles of ʟ-DOPA are designed to reduce the adverse effects using a technique known as  ‘on-off’ dosing. This being where the patient will receive a prescription for a short period and then subsequently, their dosage will be tapered off for a similar period. Due to its extensive side effects and (when administered in this ‘on-off’ fashion) the difficulties with achieving stable effects for extended periods, the drug is now only prescribed once symptoms become increasingly difficult to control and after other much safer treatment pathways have been explored.

Location of the striatum in the human brain

The second category are dopamine agonists such as pramipexole and ropinirole. These directly stimulate the dopamine receptors on nerve cells in the brain by mimicking dopamine in contrast to ʟ-DOPA which is actively converted into it. The drugs mentioned are often prescribed together as an ʟ-DOPA substitute and usually in younger patients to delay ʟ-DOPA related motor function complications. However, dopamine agonists are generally less potent than their dopamine precursor counterparts and furthermore, this class of Parkinson’s medication also comes with its own set of side effects. These include confusion, hallucinations, compulsive behaviours and leg swelling. And so although this medication offers a much safer alternative to ʟ-DOPA, it is far from a faultless solution. 

The third class of Parkinson’s medications are monoamine oxidase B (MAO-B) inhibitors such as rasagiline and selegiline. These drugs work by blocking the activity of the enzyme monoamine oxidase B - the enzyme responsible for the breakdown of dopamine in the brain. The result of this is that the effect of dopamine is prolonged as there are fewer enzymes available to metabolise it. Side effects of current MAO-B inhibitor treatments include nausea, constipation and hallucinations (although the latter is usually only seen in the very elderly). This class of drug offers moderate improvements to Parkinson’s symptoms but due to their lack of strong efficacy and minimal neuroprotective potential, they are usually used either as an early monotherapy or in conjunction to ʟ-DOPA during the periods of low dosage to minimise ‘time off’. Dopamine agonists are more predictable in their effects and are therefore safer for the patient, but limited by side effects and lack of potency.

The mechanisms of ʟ-DOPA, Dopamine agonist and MAO-B inhibitor medications

The fourth class are catechol-o-methyltransferase (COMT) inhibitors which include the drugs tolcapone and opicapone. These operate in a similar way to the previous class of MAO-B inhibitors, but inhibiting the COMT enzyme instead. This enzyme metabolises levodopa in the peripheral tissues of the body, prolonging its halflife in the bloodstream. This elevates its efficacy and reduces motor fluctuations that can arise due to changes in ʟ-DOPA concentrations in the blood. However, COMT inhibitors cannot solely manage the symptoms of Parkinson’s and are instead prescribed in conjunction with ʟ-DOPA to reduce ‘off’ time between doses. In addition, they can be used to reduce the frequency and dosage of ʟ-DOPA. However this does correlate to a reduction in risk of dyskinesia, as while the dosage of ʟ-DOPA can be diminished, its time in the bloodstream is prolonged for each dose. Furthermore, COMT inhibitors come with their own set of side-effects mainly resulting in hepatotoxicity. This being due to their interference with the normal functions of catecholamines in the liver, which can result in liver failure.

Lastly, the final main group of Parkinson’s medications are anticholinergics, such as benztropine and trihexyphenidyl. They block the muscarinic receptors from acetylcholine - a neurotransmitter in the brain responsible for the nerve impulses that cause involuntary muscle movements. This class of drugs offers mild alleviation from specific Parkinson’s symptoms like tremors and dystonia (cramping) associated with the ‘off’ periods of ʟ-DOPA dosing, but is rarely prescribed due to its adverse effects and minimal risk-to-reward ratio. It can lead to mild side effects such as a dry mouth but more significantly, new research published from the Parkinson’s Foundation in their clinical study The Parkinson’s Project found that anticholinergics were linked to cognitive impairment especially in the over-70s. And so its prescription is rarely seen except as a last resort.

The current treatment options for Parkinson’s disease are all somewhat imperfect, either offering minimal symptom relief or presenting risks of dangerous side-effects, with most typically being a mix of both. However, a South Korean company named Neurobiogen is on course to disrupt this status quo, publishing a paper[1] detailing their discovery of a new Parkinson’s medication called KDS2010. Since this initial discovery in 2021, KDS2010 has made its way through several early clinical testing phases, yielding extremely promising results. Not only have early primate testing and current phase one clinical trials shown exceptional results, but the synthesis of this potentially groundbreaking drug is relatively simple too. This could contribute to not only a highly effective medicine but a much cheaper one as well, the likes of which has become increasingly important during these times of global economic hardship.

KDS2010 falls under the MAO-B inhibitor classification of Parkinson's medication, but noticeably distinguishes itself from this family of medications in a number of ways. Firstly, although many MAO-B inhibitor medications (such as rasagiline) have been shown to alleviate symptoms of Parkinson’s by increasing dopamine levels, they are known to have poor neuroprotective properties. However, in the case of KDS2010, according to the aforementioned paper, it has been shown to demonstrate ‘significant neuroprotective and anti-neuroinflammatory efficacy against striatal pathway destruction’. The paper detailed how treatment with KDS2010 in primates 'alleviated Parkinsonian motor dysfunction’ with it moreover showing ‘virtually no toxicity or side effects in non-human primates’. Admittedly, the only published research into the drug has been undertaken as far as primate testing. But the results of these tests do strongly suggest that KDS2010 shows very promising therapeutic effects. Many suggest that this drug, once cleared for human use, could be a next-generation therapeutic candidate for Parkinson’s disease offering unprecedented levels of therapeutic care. Nevertheless, only the results of the ongoing clinical trials can confirm what initial tests have predicted, but at present, its clinical efficacy seems extremely likely.

The effect that this medication would have on the current landscape of Parkinson’s treatment if approved cannot be overstated. For one, it would offer a medicinal solution to the disease without the plethora of side effects that the current drugs offer. Dyskinesia due to ʟ-DOPA usage and periods of ‘on-off’ dosages would no longer pose a challenge to overcome. The 10 million people currently suffering from this chronic condition would be able to benefit from its promising therapeutic effects, with many regaining jobs or coming out of care. Furthermore, the simplicity of its synthesis further adds to its appeal as a new medication. While many modern medications require complex expensive syntheses with many difficult and expensive steps, KDS2010’s synthesis is made up of just 2 steps with three relatively cheap component molecules offering a 70% yield as reported in literature, which is almost guaranteed to increase as the drug grows out of its infancy.

The synthesis of KDS2010 as reported by Neurobiogen [Step one involves a suzuki reaction of 4-bromobenzaldehyde with 4’-(Trifluoromethyl)phenylboronic acid in the presence of a Pd(PPh3)4 catalyst and a base (Na2CO3) in toluene, Step two takes the 4’-(Trifluoromethyl)-[1,1’-biphenyl]-4-carbaldehyde product and reacts it with L-Alaninamide in the presence of a Sodium Cyanoborohydride reagent in glacial acetic acid]

To summarise, although the current treatment landscape for Parkinson’s disease is extensive, no drug seems to offer a fully safe and fully effective treatment to counteract its debilitating symptoms. In the coming years, KDS2010 seeks to change that and although the drug is only just starting its clinical trials phase, all the hallmarks of a safe and groundbreakingly effective drug are present. If successful, a quantum leap in Parkinson’s treatment would be made, offering a new lease of life for those afflicted.

*Main classes, there are some other medications that do not fall under any of these.

[1] Nam MH et al. KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease. Neurotherapeutics. 2021 Jul;18(3):1729-1747