Structure-Guided Optimization of α-Conotoxins Yields Potent and Selective Inhibitors of the Human α6β4 nAChR for Nicotine Addiction

Nicotinic acetylcholine receptors (nAChRs) containing the α6 subunit represent a promising therapeutic target for nicotine addiction. By employing structure-guided optimization of these α-conotoxin leads, we developed potent and selective inhibitors of the human α6β4 nAChR subtype, achieving single-digit nanomolar potency and >40-fold selectivity over related nAChR subtypes. The lead compound demonstrated enhanced enzyme stability and, in a nicotine-induced conditioned place preference model in mice, effectively attenuated addictive behaviors. These results present a novel, potent and selective α6β4 nAChR antagonist with significant potential as a therapeutic candidate for nicotine use disorder.