ja3011379_si_001.pdf (305.24 kB)

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

Download (305.24 kB)
journal contribution
posted on 18.07.2012, 00:00 by Ximena Da Silva Tavares, Angela P. Blum, Darren T. Nakamura, Nyssa L. Puskar, Jai A. P. Shanata, Henry A. Lester, Dennis A. Dougherty
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.

History