September 30, 2011

Drug-like molecules aimed at improving treatment of Parkinson’s

Drug-like molecules described by Vanderbilt researchers could lead to Parkinson’s treatments with fewer side effects.


Researchers at Vanderbilt University Medical Center have achieved a milestone in the development of a potential new treatment for Parkinson’s disease that may improve on some of the limitations of current therapy.

Three drug-like molecules that act on a specific glutamate receptor in the brain are ready for the next stage of preclinical testing prior to entering human trials. The molecules were developed with major support from The Michael J. Fox Foundation for Parkinson’s Research.

If all goes well in final preclinical testing, the molecules could be ready for clinical testing as soon as 2013, says Jeffrey Conn, director of the Vanderbilt Center for Neuroscience Drug Discovery. “[lquote]We are very excited to reach this major milestone and are eager to fully understand the extent of benefit that this new treatment strategy will have in patients suffering from Parkinson’s disease,” Conn said.[/lquote]

“Our Foundation is committed to advancing improved symptomatic therapies that could dramatically increase patients’ quality of life,” said Fox Foundation CEO Todd Sherer. “The emergence of successful drug candidates from our partnership … points to the viability of a new model for drug development, one in which academic teams collaborating with forward-thinking funding partners can help keep the pipeline flowing with promising new agents.”

New models are urgently needed as pharmaceutical companies increasingly struggle to recoup their research investments in the development of new treatments. It can cost over a billion dollars to bring a drug to market. Some pharma firms already are downsizing their research operations as patent protection ends for some of their best-selling brand name products. Cuts in health care reimbursement for medications could bring even more financial challenges for the drugmakers.

Parkinson’s disease and the shortcomings of current treatments

An estimated 1 million Americans have Parkinson’s disease, a progressive brain disorder characterized by resting tremor, rigidity and slowness of movement, as well as a battery of non-motor symptoms. It is caused by the death of nerve cells in a specific brain region that produce the neurotransmitter dopamine.

Dopamine replacement therapy, today’s gold standard treatment for Parkinson’s, relieves some motor symptoms of the disease, but over time it causes debilitating side effects such as involuntary, uncontrollable movements (dyskinesia). It is believed that dyskinesia is caused at least in part by the ebb and flow of dopamine levels in the brains of those receiving dopamine replacement therapy. Current Parkinson’s treatments also provide less and less benefit to patients as the disease worsens over the long term.

The new Vanderbilt compounds work in a fundamentally different way from dopamine replacement therapy, by bypassing the dopamine system altogether and instead modulating another of the brain’s neurotransmitters, glutamate. Conn and his colleagues have been working to activate a specific glutamate receptor called mGlu4.

The compounds are known as “positive allosteric modulators,” or PAMs. To increase mGluR4 activity while minimizing the likelihood of adverse effects, Conn’s team has taken a subtle approach to manipulating the mGluR4 receptor. “You can liken it to a dimmer switch on a light in your home, where you can turn up the gain of the receptor and its activity, or turn it down, without completely activating it or shutting it off,” Conn explained in a 2009 interview.

In their latest findings, the Vanderbilt researchers describe three PAMs that, when given systemically in a preclinical model of Parkinson’s disease, reach the brain and relieve motor symptoms, including rigidity and akinesia (a “freezing” of certain motor muscles).

NIH support

Conn’s colleagues in this effort include Craig Lindsley, co-director of the Center for Neuroscience Drug Discovery and director of medicinal chemistry; Carrie Jones, the center’s director of behavioral pharmacology; Colleen Niswender, director of molecular pharmacology; J. Scott Daniels, director of drug metabolism and pharmacokinetics; and Corey Hopkins, research assistant professor of pharmacology and chemistry.

Drug discovery leaders
Leaders of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD) are, from left, Colleen M. Niswender, director of molecular pharmacology; P. Jeffrey Conn, VCNDD director; Craig W. Lindsley, VCNDD co-director and director of medicinal chemistry; J. Scott Daniels, director of drug metabolism and pharmacokinetics (seated); and Carrie Jones, director of behavioral pharmacology. (Dana Thomas/Vanderbilt University)

Their work has been supported since 2007 by more than $4 million, largely awarded under MJFF’s LEAPS (Linked Efforts to Accelerate Parkinson’s Solutions) initiative, which assembles teams of researchers with the various expertise required to bring a particular project to fruition, and to do so in as efficient and streamlined a way as possible. Conn’s speedy results are an example of a successful LEAPS project in action.

Conn’s work on Parkinson’s disease actually began in the 1990s when he was at Emory University. That research was conducted as part of a Morris K. Udall Center of Excellence in Parkinson’s Disease Research supported by the National Institute of Neurological Disorders and Stroke (NINDS).

In 2010, he and his colleagues began a partnership with a new NINDS Udall Center at Emory to explore additional allosteric modulators as potential treatments for Parkinson’s disease.

“A primary goal of the NINDS Udall Centers program is to foster translation of research observations into improved treatments for Parkinson’s disease,” said Beth-Anne Sieber, a program director at NINDS. “We are pleased to support Dr. Conn’s discovery efforts as part of this program.”

The Vanderbilt-Fox Foundation partnership is an example of how academic medical centers are helping to fill the “drug pipeline” with new agents that potentially will dramatically improve the health of millions of patients worldwide.