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首页> 外文期刊>Biochemistry >Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor
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Novel Positive Allosteric Modulators of the Human α7 Nicotinic Acetylcholine Receptor

机译：人α7烟碱乙酰胆碱受体的新型正变构调节剂。

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摘要

The pharmacological activity of a series of novel amide derivatives wasncharacterized on several nicotinic acetylcholine receptors (AChRs). Ca2þ influxnresults indicate that these compounds are not agonists of the human (h) R4β2, R3β4,nR7, and R1β1γδ AChRs; compounds 2u00014 are specific positive allosteric modulatorsn(PAMs) of hR7 AChRs, whereas compounds 1u00014, 7, and 12 are noncompetitivenantagonists of the other AChRs. Radioligand binding results indicate that PAMs donnot inhibit binding of [3H]methyllycaconitine but enhance binding of [3H]epibatidinento hR7 AChRs, indicating that these compounds do not directly, but allosterically,ninteract with the hR7 agonist sites. Additional competition binding results indicatenthat the antagonistic action mediated by these compounds is produced by directninteraction with neither the phencyclidine site in the Torpedo AChR ion channel nornthe imipramine and the agonist sites in the hR4β2 and hR3β4 AChRs. Molecularndynamics and docking results suggest that the binding site for compounds 2u00014 isnmainly located in the inner β-sheet of the hR7u0001R7 interface, ∼12 Å from the agonist locus. Hydrogen bond interactions betweennthe amide group of the PAMs and the hR7 AChR binding site are found to be critical for their activity. The dual PAM andnantagonistic activities elicited by compounds 2u00014 might be therapeutically important.
机译：一系列新型酰胺衍生物的药理活性表征于几种烟碱乙酰胆碱受体（AChRs）。 Ca 2+流入的结果表明这些化合物不是人（h）R4β2，R3β4，nR7和R1β1γδAChRs的激动剂。化合物2u00014是hR7 AChR的特异性正构构调节剂n（PAM），而化合物1u00014、7和12是其他AChR的非竞争性拮抗剂。放射性配体结合结果表明，PAMs不会抑制[3H]甲基lycaconitine的结合，但会增强[3H] epibatidinen与hR7 AChRs的结合，表明这些化合物与hR7激动剂位点不直接但具有同构关系。其他竞争结合结果表明，由这些化合物介导的拮抗作用不是通过与鱼雷AChR离子通道中的苯环啶位点，也不与hR4β2和hR3β4AChRs中的丙咪嗪和激动剂位点直接相互作用而产生的。分子动力学和对接结果表明，化合物2u00014的结合位点主要位于hR7u0001R7界面的内部β-折叠中，距离激动剂基因座约12Å。发现PAM的酰胺基团与hR7 AChR结合位点之间的氢键相互作用对其活性至关重要。化合物2u00014引起的双重PAM和拮抗活性可能在治疗上很重要。

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  • 来源
    《Biochemistry》 |2011年第23期|p.5263-5278|共16页
  • 作者

    Hugo R. Arias Ruo-Xu Gu Dominik Feuerbach Bao-Bao Guo Yong Ye and Dong-Qing Wei;

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    †Luc Montagnier BioMedical Research Institute and National Key Laboratory of Microbial Metabolism, College of Life Sciencesand Biotechnology, Shanghai Jiao Tong University, Shanghai, China‡Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, Arizona 85308, United States§Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland)Laboratory of Chemical Biology, Department of Chemistry, Zhengzhou University, Zhengzhou, Henan, China;

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