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 and costs the economy tens of billions of dollars every year. Current therapies include nicotine replacement with a patch or gum, inhibition of the dopamine system with bupropion, and partial activation of the 42 neuronal nicotinic acetylcholine receptor (nAChR) with varenicline. None of these have been particularly effective upon initial use, and even in the cases of initial success relapse rates are nearly 80% regardless of the treatment drugs or therapies. Additional therapies in clinical trials include the non-selective nAChR antagonist mecamylamine, nicotine antibodies, and behavior modification. The nAChR most closely associated with the addictive nature of cigarettes is the 42 nAChR. Activation of thi receptor is considered to be the primary mediator of nicotine reward and the selective but low affinity 42 nAChR antagonist DHE has been demonstrated to block nicotine self-administration in rodent models. However, there are very few high affinity and selective 42 antagonists available to examine as smoking cessation medications. Starting from a small molecule combinatorial library containing more than 5 million individual compounds, we have identified selective nAChR compounds. With funding from our Phase I application we have identified lead compounds with very high affinity, potency and selectivity, both with respect to binding affinity and in vitro functional activity, at the 42 nAChR. Both of these compounds ae full antagonists at 42 nAChRs. One compound has been demonstrated to attenuate nicotine self-administration and reinstatement in rats. In this Phase II SBIR, we propose to optimize our lead compounds to further improve drug-like properties, while maintaining or improving affinity and selectivity. In Specific Aim 1, similar to a traditional drug discovery "hit-to-lead" process, additional SAR will be conducted to improve the PK/PD properties of our current lead compounds. This aim will include medicinal chemistry and coupled with in vitro affinity and efficacy testing along with the pharmacological profiling to identify drug-like compounds. Specific Aim 2 will be similar to the "lead to development" process within drug discovery, in which selected high affinity and selective antagonists will be tested in a battery of in vitro and n vivo assays to determine oral bioavailability, stability, blood brain barrier penetration, pharmacokinetics, and hERG inhibition. In addition to determining in vivo efficacy for ability to block nicotine self-administration and reinstatement in rats, this aim will include the determination of additional pharmacological effects on locomotion, anxiety, depression, and reward/aversion, in order to choose compounds to move forward to future IND-enabling toxicology.