To address the devastating effects of drug addiction, this project aims to deliver three potential drug candidates for further development and eventual clinical application. Drugs of abuse have differing mechanisms of action, but share a common pathway toward physical dependency. The mesolimbic dopamine pathway is widely accepted as a central pathway in producing the rewarding effects of addictive drugs. This pathway includes the dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc). All drugs of abuse, regardless of their mechanisms of actions, converge on the VTA-NAc pathway. Acute exposure to addictive drugs results in the elevation of dopamine levels, a reward signaling event, which promotes repeated drug intake. Addiction is then reinforced by the drugs producing a negative emotional symptom when the drug is removed. Sensitization and associative learning toward drug-related environmental cues also reinforce addiction. The nicotinic cholinergic receptors (nAChRs) may be an important target for the treatment of multiple addictions, not just nicotine. Activation of the central nAChRs has been shown to also mediate the reinforcing effects of other drugs of abuse including alcohol and cocaine. The 1422 subtype of nicotinic cholinergic receptors are implicated in the addictive properties of nicotine. Nicotine is an agonist of nAChRs, and has a dual mode of activation and desensitization. Until recently, these two modes of activation and desensitization could not be decoupled. Sazetidine A, a novel small molecule ligand of nAChR, does just this, selectively desensitizes 1422 receptors without first activating them. Preliminary data suggest that this molecule may indeed prove to be an interesting drug for treating addiction. Unfortunately, sazetidine A has poor physicochemical properties for further drug development. Sazetidine A has a relatively low log P value, a high polar surface area (PSA) value, and is a viscous oil. The low log P and high PSA suggest sazetidine A will not be readily absorbed in vivo and will have a low probability of crossing the blood-brain barrier. The lack of crystallinity poses problems in manufacturing this compound for further drug development. The aims of this proposal are to design and synthesize new 1422-selective desensitizers with the following improved physicochemical properties: 1. optimal log P value between 2 and 5;2. reduced PSA of approximately 60 E2;and 3. crystallinity with a melting point greater than 150 0C. PUBLIC HEALTH RELEVANCE: Drug addiction is a chronic brain disease with devastating societal impact. Since drug addiction has traditionally been viewed as a social problem, not a health problem, there is a disparity in effective medical treatment options. This proposal is directed at addressing this disparity by providing new therapeutic agents for medical intervention of drug abuse.