Tobacco use and nicotine addiction are an immense burden on the public health. There are an estimated 44.5 million (21%) adult smokers and an estimated 3.75 million (22%) high school student smokers in the US. Tobacco use is responsible for over 440,000 deaths per year in the US, which accounts for 1 in every 5 total deaths. Approximately 70% of the adult smokers want to quit. However, only 5-10% succeeds each year. Their inability to quit, even with full understanding of the negative health consequences, is testament to the addicting power of nicotine. Numerous studies showed that neuronal nicotinic acetylcholine receptors (nAChRs) are major mediators in brain for the development of addiction to smoking. Among major nAChR subtypes in brain, nAChRs containing both a4 and ?2 subunits are essential for nicotine addiction. The current leading treatment for nicotine addiction is nicotine replacement therapy. However, with meager success rates of 10-20%, new therapies are greatly needed. Very recently, Pfizer's Chantix(r) (varenicline) was approved by the FDA as a smoking cessation drug. Varenicline is a partial agonist at the a4?2 nAChR subtype. Clinical trials showed that varenicline helped up to 45% of smokers stay smoke free for up to 12 weeks. This result validates the a4?2 subtype as a target for smoking cessation. However, varenicline has almost full agonist activity at the a3?4 and a7 subtypes, which may lead to side effects such as nausea seen in 30% of the patients. For any disease state as prevalent as nicotine addiction, it is essential to have a number of treatment options. Acenta Discovery and its collaborators have embarked on the goal to develop alternative a4?2-selective nAChR ligands as a treatment for smoking cessation. A series of such ligands have previously been prepared that bear at C3 of their pyridine ring an azetidine or pyrrolidine connected through a CH2O linker, and a lipophilic side chain on C5. Many of these ligands are very potent and selective. One lead, sazetidine-A, exhibits subnanomolar binding affinity and >104-fold selectivity for the a4?2 over the ganglionic a3?4 subtype. Pharmacologically, sazetidine-A is quite novel as a 'silent desensitizer'. It desensitizes a4?2 nAChRs without activating them and maintains them in their desensitized state. Functional assays revealed that sazetidine-A, in contrast to varenicline, does not show agonist activity at either the a4?2 or a3?4 nAChR subtypes. Notably, initial work in animals revealed that it also has nicotine-like discriminative stimulus effects. With this unique lead compound, we would like the opportunity to study in more detail the SAR for sazetidine-A. The goals of this proposal are: (1) design and synthesize a series of sazetidine-A analogs based on preliminary data; (2) assay the analogs for binding and function with an array of nAChR subtypes; (3) select the most promising analogs for nicotine discrimination animal experiments. Ideally, this work will lead into the development of new a4?2 subtype selective nicotinic ligands to be used for smoking cessation therapy. ? ? ?