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

Tavares, Ximena Da Silva and Blum, Angela P. and Nakamura, Darren T. and Puskar, Nyssa L. and Shanata, Jai A. P. and Lester, Henry A. and Dougherty, Dennis A. (2012) Variations in Binding Among Several Agonists at Two Stoichiometries of the Neuronal, α4β2 Nicotinic Receptor. Journal of the American Chemical Society, 134 (28). pp. 11474-11480. ISSN 0002-7863. PMCID PMC3399941. doi:10.1021/ja3011379.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Received: February 14, 2012; Published: June 20, 2012. This work was supported by the National Institutes of Health [Grants NS34407 NS11756] and by the California Tobacco-Related Disease Research Program of the University of California, Award 19XT-0102.
Funding AgencyGrant Number
California Tobacco-Related Disease Research Program19XT-0102
Issue or Number:28
PubMed Central ID:PMC3399941
Record Number:CaltechAUTHORS:20120824-131040943
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Official Citation:Variations in Binding Among Several Agonists at Two Stoichiometries of the Neuronal, α4β2 Nicotinic Receptor Ximena Da Silva Tavares, Angela P. Blum, Darren T. Nakamura, Nyssa L. Puskar, Jai A. P. Shanata, Henry A. Lester, and Dennis A. Dougherty Journal of the American Chemical Society 2012 134 (28), 11474-11480
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:33518
Deposited By: Jason Perez
Deposited On:24 Aug 2012 21:20
Last Modified:09 Nov 2021 21:35

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