Discovering Drug-Like Probes for the α9α10 Nicotinic Acetylcholine Receptor - ABSTRACT Approximately 1 in 10 adults in the U.S. experience neuropathic pain, which is pain caused by a malfunctioning or diseased nervous system. Current treatments for neuropathic pain are only moderately effective and possess serious side effects. Therefore, there is a need for new and safer treatments for neuropathic pain. The α9α10 nicotinic acetylcholine receptor (nAChR) has been proposed as a potential target for neuropathic pain. Previous work has shown that α9-knockout mice exhibit decreased hyperalgesia in models of neuropathic pain. Additionally, antagonism of the α9α10 nAChR with α-conotoxin inhibitors reduces allodynia and hyperalgesia in rodent models. Despite this promising evidence supporting α9α10 as an analgesic target, current antagonists have poor oral bioavailability, low metabolic stability, and are non-selective. Due to poor expression in mammalian cells, previous studies of the α9α10 nAChRs have required the use of electrophysiology in oocytes, which has limited the discovery of novel α9α10 ligands. However, our group has recently developed a cell line that stably expresses α9α10, allowing us to identify and investigate new ligands for this receptor. My central hypothesis is that the development of a novel, drug-like α9α10 nAChR selective probe can be used to further the understanding of the α9α10 nAChR as a drug target. In Aim 1, I will use a structure-based approach to convert AT-1001, a partial α3β4 nAChR agonist with moderate antagonist activity at the α9α10 nAChR, into an α9α10-selective ligand. In parallel, Aim 2 applies a ligand-based approach with a lead compound identified from a high-throughput screen recently conducted by our lab. The proposed structure-activity relationship studies will focus on identifying a potent α9α10 antagonist. Upon identifying an improved α9α10 antagonist, the selectivity of this compound will be evaluated at other nAChR subtypes and central nervous system receptors. This research showcases two innovative approaches towards the development of a drug-like α9α10 nAChR selective probe as it employs tools and strategies that have not been previously used to develop ligands for this receptor and will advance the significance of the α9α10 nAChR in drug discovery.
