Background: α_2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α_2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α_2A-AR subtype of traditional drugs greatly limits their clinic usage.
Methods: A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α₂-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism.
Results: Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α_2A-AR over α_2B- and α_2C-ARs. Besides, the affinities are of similar linker length-dependence for each α₂-AR subtype. Among all the compounds tested, C10 has the highest affinity for α_2A-AR (pKi=− 7.45± 0.62), which is 12-fold and 60-fold selective over α_2B-AR and α_2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and “allosteric” sites of the α_2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99.
Conclusion: The specificity of C10 for the α_2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α_2A-AR subtype selective compounds.



中文翻译：

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对 alpha2A-肾上腺素受体的 4-氨基喹啉选择性机制的结构洞察。

背景： α2A-肾上腺素能受体（AR）是治疗中枢神经系统退行性疾病的潜在靶点，_{α2A -AR激动剂是治疗该病}的有效药物。_{然而，传统药物α 2A} -AR 亚型缺乏高选择性，极大地限制了其临床应用。
方法：通过不同的烷烃接头长度 (C2-C12) 对一系列由两个 4-氨基喹啉部分缀合的同二价 4-氨基喹啉进行表征，以确定它们对每个 α ₂ -AR 亚型的亲和力。随后，应用对接、分子动力学和诱变技术揭示了分子机制。
结果：大多数 4-氨基喹啉（4-氨基喹啉单体，C2-C6，C8-C10）对 α _2A -AR 的选择性高于对 α _2B - 和 α _2C -ARs 的选择性。_{此外，对于每个 α 2} -AR 亚型，亲和力具有相似的接头长度依赖性。在所有测试的化合物中，C10 对 α _2A -AR 的亲和力最高（p Ki=- 7.45± 0.62），其选择性分别是 α _2B -AR 和 α _2C -AR的 12 倍和 60 倍。对接和分子动力学表明 C10 同时与 α _{2A的正构和“变构”位点相互作用}-AR。F205 的突变使亲和力降低了 2 倍。潜在的变构残基包括 S90、N93、E94 和 W99。
结论： C10 对α _2A -AR 的特异性以及本研究提出的潜在正构和变构结合位点为开发新型α _2A -AR 亚型选择性化合物提供了有价值的指导。