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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.


Ximena Da Silva Tavares, Angela P Blum, Darren T Nakamura, Nyssa L Puskar, Jai A P Shanata, Henry A Lester, Dennis A Dougherty. Variations in binding among several agonists at two stoichiometries of the neuronal, α4β2 nicotinic receptor. Journal of the American Chemical Society. 2012 Jul 18;134(28):11474-80

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PMID: 22716019

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