Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation

DESCRIPTION (provided by applicant): Smoking remains the number one avoidable cause of death in the United States. Current therapies including nicotine replacement, inhibition of the dopamine system with bupropion, and partial activation of the 4 2 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline have not been particularly effective, with relapse rates at nearly 80% regardless of the treatment drugs or therapies. Furthermore, varenicline, the most efficacious drug, has serious psychiatricside effects. Clearly new treatments are needed. The nAChR most closely associated with the addictive nature of cigarettes is the 4 2 nAChR. Activation of this receptor is the primary mediator of nicotine reward and the selective but low affinity 4 2 nAChRantagonist DH E has been demonstrated to block nicotine self-administration in rodent models. Currently there are no high affinity and selective 4 2 antagonists available to examine as smoking cessation medications. Starting from a small molecule com