Tobacco smoking is a severe public health problem that exacts a high toll on both societal cost and personal suffering. More than 20 million premature deaths can be attributed to cigarette smoking over the last four decades in the US alone. While the prevalence of cigarette smoking has steadily declined, more than 42 million Americans still smoke, and this year approximately half a million people will die due to tobacco related causes. The total economic costs due to tobacco are now reaching nearly $300 billion annually.
Numerous investigations have demonstrated that smoking cessation significantly decreases the risk of smoking-related disease, mortality, and morbidity. However, current approved smoking cessation drugs have limited effectiveness and often cause adverse effects. Moreover, while therapies are initially successful, the majority of smokers relapse even after a prolonged time of abstinence. Thus, there is a great medical need for new more effective and safer therapies to help smokers quit and maintain long-term abstinence. Glutamate is one of the most important excitatory chemicals in the brain and plays a critical role in drug abuse. Nicotine is one of the primary psychoactive components of tobacco smoke. Scientific research indicates that the addictive effects of nicotine are related to increased glutamate transmission in the brain. Thus, one strategy for the development of medications to lessen nicotine dependence would be to focus on novel treatments that decrease glutamate transmission. The effects of glutamate are mediated by the activation of two types of glutamate receptors in the brain, ionotropic (iGlu) and metabotropic (mGlu) glutamate receptors. Although direct blockade of iGlu receptors has shown some efficacy in experimental animal models of nicotine dependence, serious unwanted side effects in humans are highly likely due to the widespread and essential roles of the fast-acting iGlu receptors during normal brain function.
Alternatively, efforts have been undertaken to inhibit glutamate transmission with drugs that modulate the slow-acting mGlu receptors, and these studies suggest that targeting mGlu may lead to therapeutics with fewer or no adverse effects. Recent data by our laboratories have indicated that one of the mGlu receptor subtypes, named mGlu7, represents a novel and promising target for manipulating the glutamatergic system to treat nicotine dependence. Specifically, we found that activation of mGlu7 function in mice reduced their desire to consume nicotine even when they were given stimuli (cues) that had previously caused them to seek out nicotine. These results demonstrated a viable therapeutic strategy based on mGlu7. Thus, we propose to develop the first drug-like mGlu7 activators and to use these novel compounds to validate mGlu7 as a target for the treatment of nicotine dependence. Our team of experts in mGlu-related drug discovery, pharmacology, and neurology of nicotine addiction is uniquely qualified to accomplish our objectives, which are both highly significant and responsive to TRDRP research priorities. This highly innovative approach may establish a novel drug discovery strategy that is useful not only for mGlu7, but also for additional mGlu receptors implicated in other serious conditions. We will develop mGlu7-selective compounds using state-of-the-art computational modeling and screening of millions of drug-like molecules, X-ray structural biology experiments, mGlu functional assays in cells, pharmacokinetic and toxicological analyses, and finally by assessing candidate compounds in animal models with relevance to nicotine dependence.
Success of the proposed work will afford the first drug-like mGlu7–selective activators and provide the basis for more extensive drug discovery efforts towards the development of clinical candidates for novel smoking cessation therapies, making this proposal an important research effort aimed at improving public health and wellbeing.