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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
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Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH

机译：烟碱药效团：尼古丁的吡啶N和乙酰胆碱氢键的羰基跨亚基界面连接至主链NH

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Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-rc interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcho-line, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.
机译：提出了用于烟碱激动剂的药理学模型已有四十年了。这些模型的核心是存在阳离子氮和氢键受体。现已公认，阳离子中心与保守的色氨酸具有重要的阳离子-rc相互作用，但鉴定氢键受体的供体更具挑战性。与乙酰胆碱结合蛋白结合的尼古丁的结构预测，药效团第二组分的结合伴侣是水分子，该氢分子还与受体互补亚基的骨架氢键结合。在这里，我们使用非天然氨基酸诱变结合激动剂类似物来检查这种氢键在α4β2神经元nAChR（与尼古丁成瘾最相关的受体）中是否在功能上很重要。我们发现与烟碱，乙酰胆碱，氨基甲酰胆碱和表巴替丁激动剂形成氢键的证据。这些数据代表完整的烟碱药效基团，并为设计选择性靶向这些受体的新治疗剂提供了见识。

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