Department of Pathophysiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, People's Republic of China.
Department of Pathophysiology, School of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan 646000, People's Republic of China.
Drug Des Devel Ther. 2020 Jul 3;14:2585-2594. doi: 10.2147/DDDT.S214157. eCollection 2020.
α-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α-AR subtype of traditional drugs greatly limits their clinic usage.
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 α-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism.
Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α-AR over α- and α-ARs. Besides, the affinities are of similar linker length-dependence for each α-AR subtype. Among all the compounds tested, C10 has the highest affinity for α-AR (Ki=-7.45±0.62), which is 12-fold and 60-fold selective over α-AR and α-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99.
The specificity of C10 for the α-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α-AR subtype selective compounds.
α-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，α-AR 激动剂是治疗此类疾病的有效药物。然而，传统药物对 α-AR 亚型缺乏高选择性，极大地限制了它们的临床应用。
通过不同的烷烃连接长度（C2-C12），将两个 4-氨基喹啉部分连接在一起的一系列同双价 4-氨基喹啉被用于评估其对每种 α-AR 亚型的亲和力。随后，应用对接、分子动力学和突变分析来揭示其分子机制。
大多数 4-氨基喹啉（4-氨基喹啉单体、C2-C6、C8-C10）对 α-AR 具有选择性，而对 α-和 α-AR 则没有。此外，每种 α-AR 亚型的亲和力都与连接体长度具有相似的依赖性。在所测试的所有化合物中，C10 对 α-AR 的亲和力最高（Ki=-7.45±0.62），对 α-AR 的选择性分别为 12 倍和 60 倍。对接和分子动力学表明，C10 同时与 α-AR 的正位和“变构”结合位点相互作用。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。
C10 对 α-AR 的特异性以及本研究提出的潜在的正位和变构结合位点为开发新型 α-AR 亚型选择性化合物提供了有价值的指导。
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