Smoking remains the primary preventable cause of death in the United States and throughout the world. Currently available smoking cessation medications have nonselective mechanisms of action and are not very successful, with cessation rates of only 15–40%. Nicotine, the active ingredient in tobacco smoke, is responsible for the addiction, and acts by binding to nicotinic acetylcholine receptors (nAChRs) in the brain. Of the many nAChR subtypes found in the brain, considerable genetic and pharmacological evidence links the α4β2 nAChR subtype to nicotine addiction. The newest and most effective smoking cessation medication is is an α4β2 nAChR partial agonist. Even though it is the best smoking cessation medication available, results in many patients are disappointing and product labeling contains warnings for the potential of serious side effects.. Clearly additional medications are required. Although partial agonists appear to be very selective in binding experiments, functional experiments suggest otherwise. Identification of high affinity and selective α4β2 agonists or antagonists has been difficult.
Using combinatorial libraries, scaffold ranking and position scanning strategies, Assuage has discovered new scaffolds that have produced high affinity nAChR antagonists with exquisite selectivity for α4β2 nAChR over α3β4 nAChR, with respect to both binding affinity and in vitro functional activity. These two features differentiate our compounds from those which are not very selective with respect to functional activity and offer only partial agonist activity. One compound (AP-202) has been demonstrated to attenuate both nicotine self-administration and nicotine prime induced reinstatement in rats. During our SBIR Phase I and Phase II grants considerable progress was made in identifying a scaffold with many drug-like properties and individual compounds that have high affinity and selective antagonist activity at the α4β2 nAChR, as well as in vivo efficacy in our model of nicotine self-administration