Tobacco smoking, which is greatly amplified by the addictive properties of nicotine, is the leading cause of preventable death worldwide, accounting for approximately 443,000 deaths in the United States each year (Centers for Disease Control and Prevention, 2011).
Unfortunately, the available medications (bupropion, varenicline, nicotine replacement therapies) do not appear to protect smokers from cue-induced cravings. Thus, there is considerable room for improvement and additional treatments of the various aspects of nicotine dependence to assist people to quit smoking.
When a person inhales cigarette smoke, the nicotine in the smoke is absorbed into the bloodstream and gains access to the brain within seconds. One of the pathways of nicotine action is through activation of certain receptors in brain. By activation of nicotinic acetylcholine receptors, nAChRs, nicotine increases the release of dopamine in the brain, a neurotransmitter that is responsible for feelings of pleasure and well-being. In theory, without the nicotine-induced elevation of dopamine levels, tobacco would not produce this type of reward.
Many different types of nAChR exist in the body, located in different tissues and having different functions, but all closely related in structure. It has been hypothesized that agents which increase the activity of the alpha4beta2 nAChR subtype can produce an increase in dopamine levels, counteracting the low dopamine levels that occur in the absence of nicotine during smoking cessation attempts. Varenicline (Chantix) provides this type of treatment option. However, varenicline and related molecules also cause changes of the receptor function (desensitization) that can result in severe side effects. We will attempt to develop variants of varenicline and other molecules that either partially block the receptor or enhance its activities in other ways, in order to prevent the physiological effects that make smoking cessation so difficult without causing side effects.
We will use a new chemical method for drug development known as in situ click chemistry, which uses the target (the alpha4beta2 nAChR protein) to assemble its own molecular modulator. Known agents like varenicline will be used as “anchor molecules” having linkers on them that do not react with the protein but are able to react with other molecules that bind nearby on the protein surface. These anchor molecules are incubated in the presence of the protein with collection of such small molecules. The formation of a linked molecule, which can only occur if both portions bind to the protein, creates a “biligand” that binds more tightly than either piece alone. The occurrence of a successful target-templated reaction is indicated by very sensitive mass spectrometry methods, identifying the molecule formed and allowing us to make it in quantity.
Once new biligands will be identified, they will be re-synthesized, tested, and further optimized to validate and then improve their binding affinity and selectivity. At that stage, the compounds will be regarded as advanced leads, and can then be further modified to improve drug-like properties and bioavailability while retaining efficacy. Such agents will serve as a promising starting point for the development of an alternative treatment of nicotine addiction.