New dopamine agonist may limit progression of Parkinson's disease: A discussion with Dr. Christopher Bishop

Background: A novel drug for Parkinson’s disease appears to provide better and longer-lasting relief from symptoms than current drugs, and may even limit progression the disease, according to a recent study in The British Journal of Pharmacology.

Currently, early to mid-stage Parkinson’s disease is often treated with selective dopamine-D₂ and -D₃ receptor agonists. But these drugs tend to lose efficacy in late-stage disease, calling for more frequent administration as well as the addition of other medications. Also, these agonists have no effect on disease progression.

In an effort to find more effective and disease-modifying medicine, researchers at Binghamton University–State University of New York, in Binghamton, NY, and Wayne State University in Detroit, MI, have developed a novel “multi-functional” agonist, D-512, with high affinity for dopamine-D₂ and -D₃ receptors. The researchers showed in a study in rats that the motor-stimulating properties of D-512 lasted three times as long as ropinirole, a leading D_2/3 agonist.

In addition, the D-512 molecule itself is an antioxidant—a meaningful property because a major cause of Parkinson’s disease appears to be excessive oxidative stress in movement-facilitating brain cells.

In this interview, investigator Christopher Bishop, PhD, of Binghamton University, discusses the advantages and limitations of D-512 for Parkinson’s disease. He also explains why he calls it a multi-functional agent and describes what the next steps of its development will be.

MDLinx: What led to the development of D-512? How did the compound come about?

Dr. Bishop: Our collaborator Aloke Dutta, PhD, is a medicinal chemist at Wayne State University who used known chemical structures of current medications as a backbone, as a starting point. By modifying the structures, he was able to create a series of compounds that might maintain an anti-parkinsonian profile but also gain neuroprotective qualities. This is why we have classified them as multi-functional.

MDLinx: Compared to ropinirole, how well did D-512 manifest in the brain and blood plasma?

Dr. Bishop: D-512 has very favorable pharmacokinetics. It reaches the brain easily in therapeutic doses, and compared to the current medication ropinirole, it is detectable for hours longer—a feature mirrored in its behavioral effects.

MDLinx: How did the two drugs compare in terms of akinesia (loss of voluntary movement)?

Dr. Bishop: Both drugs were found to improve motor activity and performance in our pre-clinical rat model. At comparable dose, D-512 was actually more potent and correcting for parkinsonian deficits.

MDLinx: Regarding duration of action, how much longer did D-512 last compared to ropinirole?

Dr. Bishop: Within a day, both drugs produced benefit an hour after treatment. Notably, D-512 appeared to convey improvements up to four hours post-administration while the effects of ropinirole had often waned. This would be predicted based on the pharmacokinetics.

MDLinx: How did the two drugs compare in terms of dyskinesia?

Dr. Bishop: D-512 and ropinirole both induced equivalent abnormal involuntary movements, known as dyskinesia, over weeks of treatment. Importantly, the severity of dyskinesia was quite mild compared to levodopa-induced dyskinesia in the same rat model.

MDLinx: Can you please describe D-512’s properties as an antioxidant?

Dr. Bishop: Oxidative stress is thought to be a key feature of Parkinson’s disease. The unique structure of D-512 appears to convey antioxidant actions that have been shown to attenuate disease-related cell death and may underlie its neuroprotective qualities.

MDLinx: What’s your next step for investigating this drug?

Dr. Bishop: Although we are excited by the preliminary work with this drug, there remains much work to be done. Scientifically, we still need to understand how D-512 is conveying its beneficial neuroprotective effects. From a drug development perspective, it will be important to determine the safety profile of this compound for use in humans while concurrently extending our work to other models of Parkinson’s disease that are predictive of good clinical response in patients.

About Dr. Bishop: Christopher R. Bishop, PhD, is Professor of Psychology in the Behavioral Neuroscience Program at Binghamton University–State University of New York.

This study was funded by the Michael J. Fox Foundation for Parkinson’s Research, the Center for Development and Behavioral Neuroscience at Binghamton University, and the National Institutes of Neurological Disorders and Stroke.