11:28am Tuesday 17 October 2017

Vanderbilt researchers strive to refill drug discovery pipeline for Parkinson’s disease, schizophrenia and fragile x syndrome

From left, Vanderbilt research fellows Julie Field, Ph.D., and Gregory Digby, Ph.D., discuss the results of a high-throughput screening experiment with Douglas Sheffler, Ph.D., assistant professor of Pharmacology. Multi-well plate experiments allow a large number of pharmacological tests to be conducted simultaneously in a short period of time.

From left, Vanderbilt research fellows Julie Field, Ph.D., and Gregory Digby, Ph.D., discuss the results of a high-throughput screening experiment with Douglas Sheffler, Ph.D., assistant professor of Pharmacology. Multi-well plate experiments allow a large number of pharmacological tests to be conducted simultaneously in a short period of time.

“There is a crying need for better drugs to treat people with serious brain disorders, such as Parkinson’s disease and schizophrenia, and for better ways to treat children with autism,” said Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD).

Vanderbilt is demonstrating how an academic medical center, in collaboration with corporate, foundation and government partners, can “very clearly and deliberately deliver on a full pipeline of drug candidates,” Conn said.

The advances, announced earlier this month, include the following:

Parkinson’s disease

Drug-like molecules identified at Vanderbilt that could improve on some of the limitations of current therapy have now reached development candidate status and are entering the final stage of preclinical testing with hopes of entering clinical testing as early as late 2012, Conn said.

Dopamine replacement therapy, today’s gold standard treatment, relieves some motor symptoms of Parkinson’s disease, but over time it causes debilitating side effects.

The new Vanderbilt compounds, developed with support from The Michael J. Fox Foundation for Parkinson’s Research (MJFF), bypass the dopamine system altogether and instead modulate the activity of a specific glutamate receptor called mGlu4.

In their latest findings, the Vanderbilt researchers describe three “positive allosteric modulators” 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).

Fragile X syndrome

Research conducted by the founders of Seaside Therapeutics Inc. in Cambridge, Mass., and others suggest that excessive signaling through another glutamate receptor, mGluR5, may contribute to manifestations of fragile X syndrome, which include impaired cognitive function, developmental delay, attention deficit and hyperactivity, anxiety, obsessive-compulsive and autistic behaviors.

With support from the company, the Vanderbilt researchers have developed drug candidates that may improve fragile X symptoms by “tuning down” the mGluR5 activity.

Seaside Therapeutics currently is conducting pre-clinical investigational new drug (IND) enabling studies of the compounds required by the FDA. They could be ready for human testing in 2012, said Conn, a member of the company’s advisory board.

Schizophrenia

Current anti-psychotic medications, which bind serotonin and dopamine receptors in the brain, help control hallucinations and delusions, but they provide little relief of other serious symptoms, including social withdrawal and the inability to pay attention or make decisions.

With support from the National Institute of Mental Health (NIMH), Conn and his team identified chemical compounds that work in a fundamentally different way, by inhibiting glycine transporter one (GlyT1).

This allows for more normal function of brain cells involved in schizophrenia.
In a transaction announced this month, Vanderbilt licensed the compounds to Karuna Pharmaceuticals in Boston, Mass., for further development leading to human testing.

“This work shows how publicly funded basic research can foster the identification of novel medication targets and promising candidate compounds that industry can then take forward,” said NIMH Director Thomas R. Insel, M.D.

Conn and Craig Lindsley, Ph.D., VCNDD co-director and director of Medicinal Chemistry, led the development of the new compounds for Parkinson’s disease, fragile X syndrome and schizophrenia with Carrie Jones, Ph.D., the center’s director of in vivo pharmacology, Colleen Niswender, Ph.D., director of molecular pharmacology, and J. Scott Daniels, Ph.D., director of drug metabolism and pharmacokinetics.

Also contributing to the fragile X syndrome work were Kyle Emmitte, Ph.D., research assistant professor of Pharmacology and Chemistry, and Alice Rodriguez, Ph.D., instructor in Pharmacology. Corey Hopkins, Ph.D., research assistant professor of Pharmacology and Chemistry, contributed to the Parkinson’s disease work.

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