Research findings reveal promising new anti-addiction drug

Published on May 23, 2013 at 1:21 AM · No Comments

Researchers at Johns Hopkins have unraveled the molecular foundations of cocaine's effects on the brain, and identified a compound that blocks cravings for the drug in cocaine-addicted mice. The compound, already proven safe for humans, is undergoing further animal testing in preparation for possible clinical trials in cocaine addicts, the researchers say.

"It was remarkably serendipitous that when we learned which brain pathway cocaine acts on, we already knew of a compound, CGP3466B, that blocks that specific pathway," says Solomon Snyder, M.D., a professor of neuroscience in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. "Not only did CGP3466B help confirm the details of cocaine's action, but it also may become the first drug approved to treat cocaine addiction." Details of the research appear May 22 on the website of the journal Neuron.

Snyder, who won a 1978 Lasker Award for identifying the brain's own opiate receptors, and his team have been studying the brain for decades. Twenty years ago, they discovered that the gas nitric oxide (NO) is a major player in the complex signaling network that lets our neurons coordinate activity with one another. Snyder and his team have since studied many of the proteins in that network that interact with NO, including GAPDH, a protein best known for regulating how cells store and use sugars.

A few years ago, Snyder's team and other researchers found that if NO reacts with GAPDH, GAPDH can then bind to another protein that whisks GAPDH away from its humdrum sugar metabolism tasks and into the nucleus, the cell's control center. There, depending on what other chemical signals are present, the GAPDH can either stimulate the neuron's growth or activate a self-destruct program - called apoptosis - that will kill the neuron.

In his research on GAPDH, Snyder came across a paper published in 1998 by scientists at Novartis. The company had identified a molecule, CGP3466B, that in laboratory tests protected neurons from degeneration by inhibiting apoptosis, and had tested it in clinical trials on patients with Parkinson's disease and amyotrophic lateral sclerosis, or ALS. But while the drug had few side effects, it wasn't an effective treatment for either of the diseases. Before Novartis gave up on the drug, however, its scientists investigated which molecules it interacted with in the brain, hoping to learn the reasons for its neuroprotective effects. Their only hit was GAPDH, a result that no doubt left the researchers scratching their heads, Snyder says. After all, CGP3466B seemed so promising partly because its effects were so specific - it appeared to do nothing except protect neurons from self-destructing. How would it accomplish that by acting on GAPDH, a signaling molecule with such a broad role in sugar metabolism? Though the study seemed like a dead end, the researchers published it anyway.

When Snyder saw the paper, he connected it to his team's findings, inferring that CGP3466B might work by preventing GAPDH from entering the nucleus to trigger cell death. In a study published in 2006, he and other Johns Hopkins researchers tested two compounds similar to CGP3466B to see if they would block GAPDH from triggering cell death under the types of highly stressful conditions that would normally cause apoptosis. The protective drugs worked, the team found, by disrupting with extraordinary potency the reaction between NO and GAPDH, which ultimately blocked GAPDH from binding to the protein that ferries it into the nucleus.

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