Understanding Varenicline Function via Key Receptor and Ligand Interactions

Approved by FDA in 2006, varenicline was the first nicotinic-based therapy for smoking cessation, targeting the α4β2 nicotinic acetylcholine receptor (nAChR). While inspired by cytisine, varenicline has distinct effects at both target and off-target receptors; however, despite being widely used clinically, the precise molecular interactions underpinning varenicline’s mode of action remain unclear. Using a multidisciplinary approach, the interactions that set varenicline apart from related compounds such as nicotine and cytisine have been identified. In particular, the binding site residues α4T139, α4T183, and especially β2S133 were shown to be key modulators for varenicline’s function. Substituting β2S133 with valine significantly reduced efficacy, pinpointing it as a crucial determinant. Additionally, a set of novel varenicline variants showed that the positioning of the quinoxaline moiety in varenicline is essential for receptor activation. These insights reveal a unique interaction network at α4β2 that underlies varenicline’s function, offering a deeper understanding of the ligand’s working mechanism.