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Jeff Conn, Ph.D., center, talks with Heidi Hamm, Ph.D., and Steven Gabbe, M.D., after presenting last week’s Discovery Lecture. (photo by Anne Rayner)

Clinic is key to speed new drug discovery: Conn

BY: BILL SNYDER

2/02/2007 - Where are the breakthrough drugs?

The pipeline of truly new medications has been dwindling, despite massive investment by the pharmaceutical industry, said Jeff Conn, Ph.D., professor of Pharmacology at Vanderbilt University Medical Center.

“We really need to understand the biology of the disorders … (and identify) molecular targets that may alter that biology,” Conn pointed out in his Vanderbilt Discovery Lecture on Jan. 25. “However, in doing this, it is critical that our basic science is guided by clinical research, and that we recognize that these novel targets can only be fully validated in the clinic.”

Conn, who directs the Pharmacology Department's Program in Translational Neuropharmacology and the Vanderbilt Institute of Chemical Biology's Program in Drug Discovery, has helped pioneer this new era of target identification.

He is an established leader in the field of metabotropic glutamate receptors, which play important roles in cognition, memory and movement, and in disorders such as schizophrenia, Alzheimer's and Parkinson's disease.

These receptors bind the neurotransmitter glutamate and influence other neurological circuits as well.

First at Emory University and later at Merck, Conn and his colleagues showed that activation of a particular glutamate receptor called mGluR4 “turned down” a signaling pathway in the brain involved in the abnormal movements characteristic of Parkinson's disease.

Clinical studies had suggested that surgical interruption of this pathway could significantly improve symptoms in patients. Conn wondered whether a drug that activated mGluR4 could do the same thing.

He and his colleagues tested an agonist that mimicked the action of glutamate on the receptor in a rat model of Parkinson's disease.

Within seconds after infusing the agonist into the animal's brain, the rat was freed of the muscle rigidity that is characteristic of the disease, and was able to move about normally.

Unfortunately, the agonist activated other glutamate receptors, raising the specter of serious side effects.

Conn wondered whether molecules that attach to “allosteric” sites on particular glutamate receptors could overcome this problem and avoid the side effects.

These molecules don't actually activate the receptor, but “potentiate” its response when glutamate drops into its usual binding site. In this way, they can “turn up the light” like the dimmer switch in an electrical circuit.

Intriguing idea, but it was a little too risky to pursue without direct evidence that this would be possible.

In 2003 Conn came to Vanderbilt to develop a drug discovery team that could begin to address this and related questions. He helped establish a high-throughput screening facility capable of randomly screening hundreds of thousands of small molecules for allosteric activity.

Since then, “we've identified a large number of very robust allosteric potentiators of mGluR4,” he said. They are now being tested for safety and efficacy in animals.

While Vanderbilt does not have the resources to bring a new drug to market, it can help reduce the risk for pharmaceutical companies by identifying new targets and finding compounds that act on them in a safe and effective way, Conn said.

“The one thing I love about working in an academic environment is the bar for success is … very different,” he concluded.

“We still have a primary academic mission … (but) we're also very interested in going the distance.”

For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to www.mc.vanderbilt.edu/discoveryseries.

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