Cigarette smoking is one of the largest causes of preventable death and disease in developed countries. Tobacco-related disease is responsible for approximately 440,000 deaths and $160 billion in health-related costs in the United States annually. Medications found to be effective for treating tobacco addiction are modestly efficacious at best, and are accompanied by numerous side-effects. In addition, high rates of relapse are considered the greatest obstacle to successfully treating nicotine dependence. Thus, development of therapeutics that can decrease vulnerability to relapse and thereby facilitate long-term abstinence is crucial for the effective treatment of nicotine addiction. The goal of Project 1 is an iterative medicinal chemistry program designed to discover and optimize new classes of potent and selective orexin-1 (0X1) receptor antagonists for the therapeutic treatment of nicotine addiction. Information about lead compounds guiding structure-activity-relationships (SAR) will be derived from a panel of cell-based assays designed to "functionally" characterize compounds for further use and testing in in vivo animal models of nicotine addiction as described in Projects 2 and 3. Best compounds will be profiled in vitro drug metabolism assays as described in Project 4 to prioritize compounds for in vivo use. We propose a number of potential starting points from which to develop 0X1 receptor antagonists. The primary and patent literature provides a multitude of lead molecules for SAR to begin. Additionally, a recent MLPCN HTS screening campaign has been completed looking for orexin-1 antagonists in two assay formats. Data from this screen has identified several new and novel orexin-1 receptor antagonists. Lastly, cheminformatic approaches including structure similarity searching and virtual screening of our in-house chemical files of TSRI (~750,000 small molecules) and commercial compounds will facilitate rapid hit expansion.
Current medications for treating tobacco addiction work modestly at best, and are accompanied by numerous side-effects. Hence, development of new and novel therapeutics that can decrease relapse rate and thereby facilitate long-term abstinence is crucial for the effective treatment of nicotine addiction.