Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611-7200, USA.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4145-9. doi: 10.1016/j.bmcl.2013.05.039. Epub 2013 May 23.
We introduce the term 'silent agonists' to describe ligands that can place the α7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5'-phenylanabaseine) was synthesized and identified as a new silent agonist for the α7 nAChR; it binds to the receptor but does not activate α7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C-C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the α7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of α7 nAChR ligands may constitute a new alternative for the development of α7 nAChR therapeutics.
我们引入“沉默激动剂”一词来描述那些能够使α7 烟碱型乙酰胆碱受体（nAChR）进入脱敏状态的配体，这些配体几乎或完全没有明显激活离子通道，形成一种复合物，当用变构调节剂处理时可以产生电流。KC-1（5'-苯基烟碱）被合成并鉴定为α7 nAChR 的新型沉默激动剂；它与受体结合，但单独应用时不会激活α7 nAChR 通道开放，其激动作用通过与 Xenopus oocyte 系统中的 II 型正变构调节剂 PNU-120596 共同应用来揭示。简洁的合成通过 Pd 催化的单芳基化和 N-Boc 哌啶酮的有机锂偶联反应在三步中完成。比较结构分析表明，正电荷、氢键受体和适当排列的芳环是构成α7 nAChR 沉默激动剂的一类物质所必需的。由于沉默激动剂可能作用于不涉及离子通道开放的信号通路，因此这类α7 nAChR 配体可能成为开发α7 nAChR 治疗药物的新选择。
