Biomolecular in the bush - a life sentence

The RACI Division of Biomolecular Chemistry will hold its 2013 conference in the Blue Mountains in July. With themes of medicinal chemistry, chemical biology and drug discovery, here is a taste of what the meeting has in store.

Associate Professor Matthew Piggott, from the School of Chemistry and Biochemistry at the University of Western Australia, recently received recognition for his work on the design of small molecule therapeutics to improve quality of life for sufferers of Parkinson’s disease when he received the 2012 Biota Award for Medicinal Chemistry.

Piggott first became interested in Parkinson’s disease during his honours year in 1996 when his father was diagnosed with the disorder. Since then a large part of his work in medicinal chemistry has been directed towards this debilitating disease.

At age 40, Piggott’s father was a ‘young onset’ Parkinson’s disease patient - the disease usually manifests in older people, with incidence rising progressively with age.

“I turn 40 next year,” said Piggott, although he clarified that his father has the idiopathic form of the disease where there is no known cause and it is rare that the disease has a simple genetic origin.

A progressive disease

Parkinson’s is a progressive neurodegenerative disease that is characterised by the death of dopaminergic neurons in the substantia nigra area of the brain. This decrease of dopamine in the brain results in people with Parkinson’s having a great deal of difficulty moving. Thus, treatment aims to increase this neurotransmitter and thereby restore normal movement.

Treatment usually begins with dopamine agonists, which are initially effective at dealing with the symptoms. However, side effects have been observed in some patients.

“Some patients become more compulsive or obsessive,” said Piggott. “For example, they can suddenly develop an addiction to gambling.” And, over time, patients’ dopamine agonists lose their efficacy.

Most patients then go onto levodopa (L-DOPA) therapy - the mainstay treatment for Parkinson’s disease. L-DOPA is the precursor to the catecholamine neurotransmitters, one of which is dopamine.

Treatment with L-DOPA restores patients’ movement but over time they commonly develop side effects. The most notable of these are the involuntary movements known as L-DOPA-induced dyskinesia and a reduction in therapeutic duration or ‘on-time’. That is, a reduction in the period of time that the patient is able to move as a result of their L-DOPA treatment. When the drug runs out, the patient is ‘off’ or unable to move very well, or at all, depending on the severity of the disease.

Dealing with side effects

Piggott’s work is focused on addressing the side effects cause by L-DOPA, the main one being dyskinesia. These jerky, involuntary movements are often mistakenly thought to be a symptom of Parkinson’s disease, when in fact they are a side effect of the treatment.

“This dyskinesia tends to develop faster in younger-onset patients,” added Piggott.

One current treatment for dyskinesia in these patients is deep brain stimulation. This involves inserting two electrodes into the brain and electrically stimulating that part of the brain involved in creating the involuntary movements. “It has a high success rate,” said Piggott. “It can be very effective in reducing dyskinesia, but it is extremely expensive and strokes, leading to further impairment to movement, speech, or resulting in personality changes are an unlikely but real possibility.”

The only other current option for these patients to get relief from these jerky, involuntary movements is by taking a drug called amantadine, which has limited efficacy, does not work for many patients and has side effects of its own. Hence, Piggott’s work on developing a pharmaceutical option to treat this problem for patients.

“It has been known for some time now that the illicit drug most commonly known as ecstasy, methylenedioxymethamphetamine (MDMA), ameliorates the side effects of L-DOPA in animal models of Parkinson’s disease, and anecdotally in humans,” said Piggott.

But MDMA has little therapeutic potential in this context because it makes users ‘high’, and whether it is safe to use in humans over the long term is unclear. “Although controversial, there is evidence that MDMA may be neurotoxic, or at least responsible for long-term, deleterious changes in brain chemistry.”

Modifying MDMA

In collaboration with Dr Jonathan Brotchie, from the University Health Network in Toronto, Canada, Piggott’s team has set out to create MDMA analogues and show that it is possible to dissociate the beneficial effects of MDMA from its undesirable attributes.

“The best compound, which we call UWA-101, is even more effective than MDMA at enhancing the quality of levodopa therapy. In the best animal model of Parkinson’s disease, a primate model, UWA-101 lengthened on-time by up to 30%.

“More importantly, UWA-101 increased the proportion of on-time that was of good quality (ie, without disabling dyskinesia) by 178%. If translated to a medicine, this would mean that Parkinson’s patients could take their medication less frequently and get a better quality result from it,” Piggott explained.

UWA psychopharmacologist Professor Mathew Martin-Iverson and PhD student Zak Millar, have shown that UWA-101 is unlikely to be psychoactive, based on studies in rats. “These studies include examining how the drug affects rats’ response to startling noises and whether they can be trained to discriminate UWA-101 from MDMA,” Piggott said.

In addition, UWA-101 is not toxic to a cell line used to model MDMA-induced neurotoxicity. “Longer-term studies in animals are required to confirm a lack of neurotoxicity,” Piggott admitted.

An estimated 80,000 Australians live with Parkinson’s. Most people with the disease continue to live interactive and rewarding lives. Piggott attests to this with his father continuing to lead an engaging life despite his disease. But there is no doubt that Parkinson’s makes many things difficult, and some things impossible, for most sufferers.

“My father turns 60 this year,” he said. “People die with this disease, not from it - that’s why it’s been described as a life sentence, not a death sentence.”

Associate Professor Matthew Piggott with PhD student Michael Gandy holding a model of MDMA and discussing how it might be modified. Credit: Bob Bucat.

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The Royal Australian Chemistry Institute Division of Biomolecular Chemistry will hold its 2013 conference - Biomolecular in the Bush - at the Fairmont Resort in the Blue Mountains on 14-17 July.

For more information, go to the conference website at www.raci-bio-conf.org.

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