Alternative tobacco cessation agents are needed due to the high rate of relapse with currently available pharmacotherapies. The overall goal of the current Phase II STTR grant application is to provide supporting data towards the development of the natural product, R(+)-nornicotine, as an orally-effective, alternative tobacco use cessation agent. Smokers are also exposed to alkaloidal nornicotine from tobacco and as a nicotine metabolite. Compared to nicotine, nornicotine has a long residence time in brain and a unique pharmacological profile. Recent data from our laboratory demonstrate that R(+)-nornicotine is more potent than S(-)-nornicotine in stimulating dopamine (DA) release from rat nucleus accumbens slices in vitro, and that the efficacy of R(+)-nornicotine in this assay is less than that of both S(-)-nicotine and S(-)-nornicotine, suggesting that R(+)-nornicotine is a partial agonist at nicotinic receptor subtypes (a6-containing) mediating DA release. Importantly, we found that R(+)-nornicotine decreased i.v. nicotine self-administration more potently than S(-)-nornicotine in rats. These preclinical results set the stage for determining the potential therapeutic benefit of R(+)-nornicotine as a tobacco use cessation agent in humans. Toward this goal, Yaupon Therapeutics, Inc., is close to the stage at which an Investigational New Drug (IND) application to the FDA can be submitted to conduct a Phase 1 human clinical trial with R(+)-nornicotine. The proposed studies will fully assess the oral bioavailability of R(+)-nornicotine. In addition, as part of the FDA requirements, preclinical toxicology will be performed to provide safety information as part of the IND submission requirements. Following FDA approval, a Phase 1 safety study of oral R(+)-nornicotine will be conducted using a randomized, placebo-controlled, dose-escalation design in healthy tobacco smokers who are exposed regularly to nornicotine as a result of smoking behavior. This safety study will be conducted in the General Clinical Research Center (GCRC) at the University of Kentucky Chandler Medical Center. The cardiovascular, performance and subjective effects of R(+)-nornicotine will be measured before and at multiple time points after dose administration, and the relationship between behavioral effects and plasma R(+)-nornicotine levels will be determined. The results from this Phase 1 safety study will inform future clinical efficacy studies with R(+)-nornicotine. [unreadable] [unreadable]