Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
J Am Chem Soc. 2012 Jul 18;134(28):11474-80. doi: 10.1021/ja3011379. Epub 2012 Jul 9.
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.
已评估了四种激动剂（乙酰胆碱、尼古丁、戒烟化合物伐伦克林（Chantix）和烟碱（Tabex））与α4β2 烟碱型乙酰胆碱受体（nAChR）的 2:3 和 3:2 化学计量比的药物-受体结合相互作用。先前的研究已经确定，非天然氨基酸诱变可以探测 nAChR 上的三个关键结合相互作用：阳离子-π 相互作用和与受体蛋白骨架的两个氢键相互作用。我们发现所有药物都与受体的 TrpB 形成阳离子-π 相互作用。除了缺乏 N(+)H 基团的 ACh 之外，所有药物都与一个骨架羰基形成氢键，而 ACh 和尼古丁的行为相似，都充当氢键受体。然而，伐伦克林不是与其他三种化合物强烈相互作用的受体骨架 NH 的氢键受体。此外，我们看到与烟碱的氢键相互作用存在有趣的变化，这为该化合物的化学计量选择性提供了合理化解释。
