Selective Positive Allosteric Modulators of a4b2 Nicotinic Receptors - ABSTRACT Tobacco addiction remains a leading cause of disease and death worldwide, and an increasing number of never- smokers are being exposed to nicotine via e-cigarettes. However, the role of specific nicotinic acetylcholine receptors (nAChR) in nicotine’s behavioral effects remains poorly understood because of the availability of very few subtype-selective probes, which limit drug development potential. Thus, this proposal aims to develop novel probes to better understand the function of the different α4β2 subtypes, which have been proposed to underlie behaviors characteristic of nicotine dependence. The α4β2 nAChR subtypes exhibit two distinct isoforms: α42β23, which has a high affinity for acetylcholine and nicotine, and α43β22 nAChR, which has a lower affinity for acetylcholine and nicotine. Our recent findings have suggested that probes selectively targeting the high sensitivity α42β23 nAChRs may provide a novel, previously undefined understanding of nicotine’s behavioral and pharmacological actions. Thus, these studies will develop and optimize novel positive allosteric modulators (PAMs) of the high sensitivity α42β23 nAChRs. Specific Aim 1 will begin by focusing on the synthesis of novel analogs of desformylflustrabromine (dFBr) and GAT2802 to derive an improved pharmacological profile. Specific Aim 2 will involve in vitro characterization of novel probes from both structural classes as α42β3 nAChR-selective PAMs. Thereafter, Specific Aim 3 studies will evaluate ADME/PK profiling of key α42β23 PAMs to eliminate potential liabilities and identify probes with suitable drug-like properties. Finally, in Specific Aim 4, the most promising probes will be tested for their efficacy in inducing behaviors characteristic of nicotine’s 42 nAChR actions in adult male and female mice. Taken together, these studies will develop and validate novel HS-selective α42β23 PAM probes to better understand the pharmacological effects of α4β2 nAChRs in behaviors characteristic of nicotine’s actions, which may thereby lead to future therapeutic implications.
