Variations in Binding Among Several Agonists at Two Stoichiometries of the Neuronal, 伪4尾2 Nicotinic Receptor

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• 作者：Ximena Da Silva Tavares ; Angela P. Blum ; Darren T. Nakamura ; Nyssa L. Puskar ; Jai A. P. Shanata ; Henry A. Lester ; Dennis A. Dougherty
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：July 18, 2012
• 年：2012
• 卷：134
• 期：28
• 页码：11474-11480
• 全文大小：282K
• 年卷期：v.134,no.28(July 18, 2012)
• ISSN：1520-5126

文摘

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 伪4尾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鈭捪€ interaction, and two hydrogen-bonding interactions to the protein backbone of the receptor. We find that all drugs make a cation鈭捪€ interaction to TrpB of the receptor. All drugs except ACh, which lacks an Np>+p>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.