α6 nicotinic acetylcholine receptors: A pharmacological challenge with untapped therapeutic promise

α6-containing nicotinic acetylcholine receptors (α6∗ nAChRs), particularly the α6β2∗ and α6β4∗ subtypes, are promising therapeutic targets for neurological disorders such as nicotine addiction, Parkinson's disease, and pain. However, progress is significantly hampered by two interrelated challenges: difficulties in achieving robust functional expression in vitro and the limited availability of subtype-selective ligands. This review synthesizes the current advances in overcoming these obstacles. We detail the evolution of in vitro models, highlighting the success of engineered constructs such as chimeras and concatamers, targeted mutagenesis, and chaperone co-expression that have facilitated detailed pharmacological investigations. A central focus is on the current ligand landscape, with a critical evaluation of α-conotoxins as premier-yet-limited pharmacological probes available and the persistent challenge in developing selective small-molecule modulators. By integrating current progress in both receptor expression and ligand pharmacology, this review provides a roadmap for future research aimed at developing the specific tools required to fully exploit the therapeutic potential of α6∗ nAChRs.