Variations in binding among several agonists at two stoichiometries of the neuronal, α4β2 nicotinic receptor.
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.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Ximena Da Silva
Xda S
Tavares
Angela P
AP
Blum
Darren T
DT
Nakamura
Nyssa L
NL
Puskar
Jai A P
JA
Shanata
Henry A
HA
Lester
Dennis A
DA
Dougherty
D000818:Animals; D001665:Binding Sites; D006860:Hydrogen Bonding; D018722:Nicotinic Agonists / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2