New Drugs for Smoking Cessation to Be the Target of Grant-Funded Partnership

PASADENA, Calif.—The California Institute of Technology has been awarded a five-year grant for $4.6 million from the National Institute on Drug Abuse to develop a program for discovering medications aimed either at helping people avoid nicotine addiction or at helping smokers to quit. The project will include researchers from the University of Colorado at Boulder and from Targacept, a North Carolina-based biopharmaceutical company whose scientists are leaders in research focused on a class of receptors known as neuronal nicotinic receptors.

Henry Lester, Caltech's Bren Professor of Biology and presently chair of the Caltech faculty, is directing the project, which is called a "National Cooperative Drug Discovery Group in Smoking Cessation." Lester's group will develop new strains of mice, each exaggerating the action of a particular nicotinic receptor subtype. The researchers plan to define the behavior of the mice, and of nerve cells in these mice, as they respond to nicotine and to candidate smoking-cessation drugs.

Lester's group has already established a track record in the study of nicotine addiction. In November 2004, the Caltech and Boulder groups published an article in Science announcing experimental results with "knock-in" mice, whose receptors had been genetically engineered for hypersensitivity to nicotine. The results indicated that specific drug interventions for addressing nicotine addiction were, in principle, very possible to design.

Special mice provide a fruitful way to go about the design of new drugs because an experimental animal designed for hypersensitivity to nicotine is appropriate for tracking nicotine-dependent molecular signals within the nervous system. A goal is to find ways to block one or more of these signals to interfere with the release of dopamine, which has long been associated with pleasure and contentment. Another goal is to interfere with the molecular changes that constitute addiction itself. With the accomplishment of these goals, smoking might never become an irresistible, pleasurable habit.

"I personally believe that nicotine addiction will be among the first addictions to be solved, because we already have so many tools to study it," Lester said in 2004 after the Science paper was published.

In the new research program, the Lester group will provide "target selection" by identifying the most promising strategies for developing drugs. The Boulder group, led by Michael Marks, will conduct discovery and optimization phases by applying sophisticated biochemical measurements to the mice, further describing the response to individual drugs.

Targacept's efforts will be led by Merouane Bencherif. Targacept will identify from its compound portfolio candidate drugs that interact selectively with the applicable nicotinic receptor subtypes. Targacept designs, discovers, and develops novel compounds that act upon various subtypes to promote therapeutic effects and to limit adverse side effects. In addition to the new project in smoking cessation, Targacept's therapeutic focus is on central-nervous-system diseases and disorders such as Alzheimer's disease and other cognitive disorders, along with schizophrenia, pain, depression, and anxiety.

The National Cooperative Drug Discovery Group brings together the complementary talents of these groups to define useful approaches to smoking cessation. Advisors to the group include William Corrigall, who first proved that nicotine is addictive in animals; Allan Collins of Boulder, an expert on the genetics of nicotine and alcohol addiction; and Dennis Dougherty, Caltech's Hoag Professor of Chemistry, who has worked with Lester for years on the chemistry of neuroreceptors.

Although many complex steps occur between primary research and clinical use of a drug, the researchers hope that by studying the biology of nicotinic receptors, the compounds that act on these receptors, and their effect upon stylized animal behaviors that resemble addiction, they will define new principles applicable to smoking cessation and facilitate the development of effective new therapies.

The National Institute on Drug Abuse is part of the National Institutes of Health.