Researchers aim to boost activity of a nicotinic receptor subunit that protects against addiction.

The Scripps Research Institute and the University of Pennsylvania School of Medicine have been awarded approximately $8.2 million from the National Institute on Drug Abuse (NIDA) over five years to develop novel compounds that could eventually become drug candidates for the treatment of tobacco addiction. Of the funds awarded, $5.7 million will go to Scripps Research, and $2.5 million to the University of Pennsylvania. The research will focus on the development of novel kinds of potent and selective compounds that affect nicotinic receptors in the brain.

“We have been studying the properties of cloned human nicotinic receptor subtypes in vitro for years with the hope of using the methods and cell lines we have developed to discover new drugs for these receptors,” says Jon Martin Lindstrom, Ph.D., professor of neuroscience at the University of Pennsylvania School of Medicine. “This collaboration, and the support of NIDA, provides critical elements to turn these hopes into reality.”

Recent studies have shown that genetic variations in several nicotinic receptor subunits increase vulnerability to tobacco addiction, although initially little was actually known about these variations or their function, says Paul J. Kenny, Ph.D., an associate professor in the department of molecular therapeutics on the Jupiter, Florida campus of Scripps Research.

“We got interested in one of these lesser-studied subunits that influences smoking and have developed a good understanding of how it works in the brain,” he explains. “It seems that this subunit is part of a distinct subtype of nicotinic receptor that actually protects against tobacco addiction. Now we want to find compounds that boost the activity of this receptor subtype in the hopes that they will be effective in reducing tobacco smoking.

“This approach contrasts with most antismoking treatments today, which are aimed at reducing the positive impact of nicotine on the brain’s reward centers,” he adds. “Instead, we aim to enhance the inhibitory effects of the drug on these reward centers.”

Dr. Kenny said that he plans to use Scripps Florida’s compound-screening resources to look for compounds that Dr. Lindstrom can then test to provide a clearer understanding of how they work on the receptor subunits. The researchers then hope to conduct further studies on the effectiveness of the most promising compounds.

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