Variations in binding among several agonists at two stoichiometries of the neuronal, ?4?2 nicotinic receptor.

ABSTRACT: 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 ?4?2 nicotinic acetylcholine receptor (nAChR). Previous studies have established that unnatural amino acid mutagenesis can probe three key binding interactions at the nAChR: a cation-? interaction, and two hydrogen-bonding interactions to the protein backbone of the receptor. We find that all drugs make a cation-? 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.

SUBMITTER: Tavares Xda S 

PROVIDER: S-EPMC3399941 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature