Ligands Targeting α9-Containing Nicotinic Acetylcholine Receptors: Structure−Activity Relationships and Therapeutic Potential in Neuropathic Pain

Abstract Neuropathic pain remains a significant clinical challenge due to the varying efficacies and aversive effects associated with the currently available treatments. Most notably, the addiction potential associated with opioid use for pain presents a critical need for non-opioid-targeting analgesics. In the last two decades, α9-containing nicotinic acetylcholine receptors (nAChRs) have been evaluated preclinically for their potential as a new target for neuropathic pain therapies. In this perspective, we discuss several classes of ligands that modulate these receptors, highlighting hurdles that have arisen during their development and efforts that have been made to improve their therapeutic potential. Additionally, we consider the significant role these ligands have played in current and future drug discovery for this target.