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Understanding nicotinic receptor subtype specificity

Institution: California Institute of Technology
Investigator(s): Dennis Dougherty, BS, MS, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19XT-0102 Award: $361,036
Subject Area: Nicotine Dependence
Award Type: Exploratory/Developmental Award

Initial Award Abstract
The addictive properties of nicotine are central to the countless health problems associated with smoking. Addiction is an extraordinarily complex behavior, about which much must still be learned. The present work seeks a better understanding of the molecular interactions in the brain that lead to nicotine addiction. The goal is to provide insights that will facilitate the development of a new generation of therapeutics and associated treatments designed to help smokers quit. In the human brain there is a large family of related proteins called acetylcholine receptors that play important roles in learning and memory. These receptors are the targets of efforts to find cures for Alzheimer’s disease, Parkinson’s disease, attention deficit disorders, and schizophrenia. It is known that when nicotine enters the brain it interacts with such acetylcholine receptors. The interaction launches a signal that ultimately feeds into well-established addictive pathways in the brain. There are at least two dozen types of acetylcholine receptors in the brain, close cousins with subtle differences. However, not all acetylcholine receptors link to addictive pathways, and nicotine specifically targets only those that do. We do not at present understand how nicotine is able to specifically target acetylcholine receptors associated with addiction, while avoiding other receptors that appear to be very similar in structure. This issue provides the central focus of the proposed work. The acetylcholine receptors are complicated proteins that present special challenges for researchers. We have developed new technology that combines the powerful tools of molecular biology, organic chemistry, and computer modeling. This approach provides insights of unprecedented precision concerning drug-receptor interactions, and it is ideally suited to the issue of targeting specific receptors. Using this methodology, we will determine the structural features of nicotine and the structural features of the specific acetylcholine receptors it targets that provide the molecular basis of nicotine addiction. Along with basic information about the chemistry of nicotine addiction, the results developed here have considerable therapeutic implications. One strategy to developing new smoking cessation drugs is to develop molecules that target the same receptors as nicotine, but that do not activate them in the same way. In this way, the drugs interfere with nicotine’s actions and negate its addictive properties. The smoking-cessation drug Chantix® is the first pharmaceutical to work in this way, but, in part because of associated side effects, improved versions of this drug would be of great interest. In order to develop such drugs, we need to understand how to target the right receptors; the ones that nicotine targets. The information obtained in the present work will thus be directly relevant to efforts by the pharmaceutical industry to develop the next generation of smoking cessation medicines.