一项研究说，科学家在设计针对大脑尼古丁成瘾受体的戒烟药物方面可能得到更好的手段。尼古丁与神经受体结合并激活让信号传递到神经元的通道，但是人们只是部分理解了这一结合过程。为了审视这种结合的一个关键相互作用，Dennis Dougherty及其同事根据与尼古丁结合但是不参与大脑功能的蛋白质的结构合成了氨基酸和药物类似物。这组作者说，这种试验性的技术揭示出了这种药物和一种受体的特定亚单位的一个关键氢键，这种受体与尼古丁成瘾有很强的相关性。这组作者说，这种氢键的发现确立了关于尼古丁如何触发大脑信号的一个完整的概念模型。这组作者说，科学家可以使用这个称为“药效团“的模型作为设计执行与尼古丁相同的活动但是产生不同结果的药物的一个模板。
论文 #10-07140: "The nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of ACh hydrogen bond across a subunit interface to a backbone NH," 作者 Angela Blum, Henry Lester和Dennis Dougherty
媒体联系人： Dennis Dougherty，加州理工学院化学与化学工程系
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA
电话：626-395-6089
电子邮件：dadougherty@caltech.edu
Published online before print June 28, 2010, doi: 10.1073/pnas.1007140107
Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Angela P. Bluma, Henry A. Lesterb, and Dennis A. Doughertya,1
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-π 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, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.
