TSRI scientists awarded innovative grant to develop anti-smoking drug candidates

Mar 28 2013

As part of an unprecedented national effort to develop new drugs to treat neurological disorders, scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded an innovative grant from the National Institute of Neurological Disorders and Stroke to help people break their addiction to nicotine.

Paul Kenny, a TSRI associate professor, is the principal investigator for the new study, which aims to develop anti-smoking drug candidates to the point of Phase I clinical trials, which focus on human safety testing. Also helping to guide the work are TSRI scientists Ted Kamenecka, Patricia McDonald and Michael Cameron.

The new study is part of the National Institutes of Health (NIH) Blueprint for Neuroscience Research Grand Challenge, a collaborative effort that includes the NIH Office of the Director and the 14 NIH institutes and centers that support research on the nervous system. As part of the project, The TSRI scientists will have access to industry-style drug development services and expertise—what the NIH is calling a "virtual pharma" to help develop these new compounds.

"An innovative feature of this grant is the fact that we will have access to a panel of experts to help us advance these compounds into human testing," Kenny said. "The people on the panel are senior industry experts with considerable experience in drug development programs, who are eager for us to succeed. What's more, if the drug is successful in Phase I trials, we will receive help from the NIH in establishing appropriate relationships with industry to advance the drug into the later stages of clinical testing, and eventually to marketing a novel smoking cessation medication."

Kenny and his colleagues will be expanding their already successful investigation of a pair of neuropeptides known as hypocretin-1 and hypocretin-2 (also known as orexin-A and orexin-B), which stimulate hypocretin-1 and hypocretin-2 receptors.

Hypocretin-1 receptor activity is considered critical in maintaining tobacco addiction in human smokers. In a landmark 2008 study in the Proceedings of the National Academy of Sciences, Jonathan Hollander and colleagues in Kenny's laboratory showed that blocking hypocretin-1 receptors not only decreased nicotine use in animal models, but also blocked nicotine's stimulatory effects on brain reward circuitries considered critical in motivating tobacco use.

"We have been able to identify novel hypocretin-1 receptor antagonists that demonstrate drug-like properties, meaning that they may eventually be suitable for use in humans. This grand challenge award will allow us to further optimize these compounds and then to test whether they are safe in humans. If this proves to be the case, we believe that they will be highly effective therapeutic agents for tobacco dependence," Kenny said.

Tobacco smoking is a global scourge, killing more than 5 million people each year worldwide, according to the World Health Organization. It is estimated that if current trends continue, by 2020 smoking will become the largest single health problem worldwide. The World Bank estimates that in high-income countries, smoking-related healthcare accounts for between 6 and 15 percent of all healthcare costs, some $160 billion annually.

Nicotine addiction is notoriously hard to break. Even with the most effective smoking-cessation agents available, more than 80 percent of smokers who quit or attempt to quit will relapse.