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The drug discovery leadership team includes (front row, from left) Craig Lindsley, Ph.D., Carrie Jones, Ph.D., Colleen Niswender, Ph.D., (back row, from left) P. Jeffrey Conn, Ph.D., and J. Scott Daniels, Ph.D. (photo by Susan Urmy)

Novel grant supports drug discovery effort

BY: LEIGH MACMILLAN

3/19/2010 - A $10 million grant from the National Institute of Mental Health has established Vanderbilt's Program in Drug Discovery as a National Cooperative Drug Discovery and Development Group (NCDDDG).

The five-year grant will support efforts to find novel therapeutic agents for the treatment of schizophrenia.

“This is one of the first examples of the NIH funding a fully integrated drug discovery effort, with the large team of investigators it takes to move ideas from basic science findings all the way to novel therapeutics,” said P. Jeffrey Conn, Ph.D., director of the Vanderbilt Program in Drug Discovery and co-principal investigator with Craig Lindsley, Ph.D., director of Medicinal Chemistry, of the NCDDDG.

The program's other leaders — internationally recognized in their respective areas of drug discovery — are Carrie Jones, Ph.D., director of Behavioral Pharmacology, Colleen Niswender, Ph.D., director of Molecular Pharmacology, and J. Scott Daniels, Ph.D., director of Drug Metabolism and Pharmacokinetics.

The investigators are developing compounds for treating schizophrenia that work in fundamentally new ways. They expect that their new compounds will help all of the major symptoms domains of the disorder: the positive (hallucinations, delusions), negative (blunted affect, social withdrawal) and cognitive symptoms.

Current anti-psychotic medications do not effectively treat the negative and cognitive symptoms, which leaves many schizophrenia patients unable to live successful lives, Conn noted.

With the NCDDDG grant, the investigators will focus first on two novel drug targets, and depending on their success, they will proceed to explore a “pipeline” of additional targets.

In each case, “we have a strong rationale for believing the approach could provide a fundamental breakthrough in terms of offering real help to schizophrenia patients,” Conn said.

Their belief is based on clinical data.

In the 1950s and 60s, emergency room physicians began to see patients who were intoxicated with the street drug angel dust (PCP) and exhibited all of the major symptoms of schizophrenia.

Further studies demonstrated that PCP acts as an antagonist of the NMDA-type receptor for glutamate, the main excitatory neurotransmitter in the brain, and that other drugs that block the NMDA receptor also cause schizophrenia-like symptoms.

The findings suggested that increasing NMDA receptor function might have a beneficial effect for treating schizophrenia, and researchers were able to show this using the amino acid glycine, which activates the NMDA receptor.

“The problem was that glycine is not suitable to use as a drug, and it's been impossible to develop a molecule with drug-like properties that activates the NMDA receptor the way glycine does,” Conn said.

So Conn, Lindsley and their colleagues focused instead on developing compounds that block the glycine transporter GlyT1 — a protein that normally clears glycine from the space between neurons. GlyT1 inhibitors increase the concentrations of glycine available to activate the NMDA receptor. The NCDDDG funding will support getting the GlyT1 inhibitors to the point where they can be licensed to a company that can take them through clinical development, Conn said.

The team's second target is a receptor (M1) for the neurotransmitter acetylcholine. This receptor also increases NMDA receptor activity (through a more circuitous route compared to glycine), and here again, strong clinical data gave Conn and colleagues “a high level of confidence in the mechanism.”

In the 1990s, almost every pharmaceutical company tried to develop compounds to activate the M1 receptor (to treat the cognitive deficits of Alzheimer's disease), but these compounds all had side effects that caused them to fail. The pharmaceutical industry abandoned M1 receptors as a target.

The Vanderbilt team took a different approach. Rather than trying to find compounds that work in the traditional way to turn the M1 receptor all the way “on,” they attempted to develop compounds that work at another place on the protein. These “allosteric modulators” turn up the protein's function gradually, like a dimmer switch.

“We've discovered a new approach to activate M1 receptors very selectively,” Conn said.

Conn, Lindsley and their colleagues are pioneers in the discovery of compounds that work as allosteric modulators.

“We were out front saying this could be done, and everybody else was saying it couldn't be done. It's gratifying to me that most major pharmaceutical companies now have allosteric modulator programs going,” Conn said.

The NCDDDG grant will support efforts to chemically optimize the Vanderbilt investigators' early compounds to the point where these molecules can be advanced as drugs.

“Drug discovery is more about drug disposition and metabolism than it is about the primary target,” Conn said. “It's about optimizing compounds so they can be swallowed as pills, so they get absorbed, get into the brain, activate the receptor and don't have toxicity.

“We are fortunate to have a world class group of investigators, each of whom are established experts in the different components of a drug discovery effort that are required to advance novel molecules to a point where they can enter clinical development…that's what this grant will support.”

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