Variations in Binding Among Several Agonists at Two Stoichiometries of the Neuronal α4β2 Nicotinic Receptor

摘要

Drug-receptor binding interactions of four agonists – ACh, nicotine, and the smoking cessation compounds varenicline (Chantix®) and cytisine (Tabex®) – have been evaluated at both the 2:3 and 3:2 stoichiometries of the α4β2 nicotinic acetylcholine receptor (nAChR). Previous studies have established that unnatural amino acid mutagenesis can probe three key binding interactions at the nAChR: a cation-π interaction, and two hydrogen bonding interactions to the protein backbone of the receptor. We find that all drugs make a cation-π interaction to TrpB of the receptor. All drugs except ACh, which lacks an N⁺H group, make a hydrogen bond to a backbone carbonyl, and ACh and nicotine behave similarly in acting as a hydrogen bond acceptor. However, varenicline is not a hydrogen bond acceptor to the backbone NH that interacts strongly with the other three compounds considered. In addition, we see interesting variations in hydrogen bonding interactions with cytisine that provide a rationalization for the stoichiometry selectivity seen with this compound.