The α7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified initially as a binding site for α-bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting α7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of α7 receptors. A key feature of α7 receptors is their rapid desensitization by standard “orthosteric” agonist, and we discuss insights into the conformational landscape of α7 receptors that has been gained by the development of ligands binding to allosteric sites. Some of these sites are targeted by positive allosteric modulators that have a wide range of effects on the activation profile of the receptors. Other sites are targeted by direct allosteric agonist or antagonists. We include a perspective on the potential importance of α7 receptors for metabotropic as well as ionotropic signaling. We outline the challenges that exist for future development of drugs to target this important receptor and approaches that may be considered to address those challenges.

中文翻译：

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α7烟碱型乙酰胆碱受体的治疗靶向

α 7 型烟碱型乙酰胆碱受体是配体门控离子通道 cys-loop 超家族所有成员中最独特和最有趣的一种。由于它最初被鉴定为哺乳动物脑中α-银环蛇毒素的结合位点，后来被鉴定为具有相对高钙渗透性的功能性同源受体，因此它已被视为从阿尔茨海默病到哮喘等多种适应症的潜在治疗靶点。在这篇综述中，我们讨论了靶向α 7 受体的历史和技术现状，从亚型选择性激动剂和选择性激活α 7 受体的基本药效团开始。α的一个关键特征7 受体是它们通过标准“正构”激动剂的快速脱敏，我们讨论了通过开发与变构位点结合的配体而获得的α 7 受体构象景观的见解。其中一些位点被正向变构调节剂靶向，这些调节剂对受体的激活谱有广泛的影响。其他位点由直接变构激动剂或拮抗剂靶向。我们对α 7 受体对代谢型和离子型信号传导的潜在重要性进行了展望。我们概述了未来开发针对这一重要受体的药物所面临的挑战，以及可以考虑解决这些挑战的方法。