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Structural insight into the mechanism of 4-aminoquinolines selectivity for the alpha2A-adrenoceptor

By Zaibing Li, Jingyu Li, Liyan Liu, Wenyi Deng, Wen Zhang, Huifang Hou, Xinyuan Wang, Zhimei Yang, Xiaoying Wang, Shanze Chen, Yi Wang, Junli Chen, Ning Huang

Posted 27 Feb 2019
bioRxiv DOI: 10.1101/561894 (published DOI: 10.2147/DDDT.S214157)

α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are one of the most effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage. In this study, 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. Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for the α2A-AR over α2B- and α2C-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 the α2A-AR (pKi=-7.45±0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics studies suggest that C10 simultaneously interacts with an orthosteric and an “allosteric site” of the α2A-AR. The mutation of F205, which is situated at the orthosteric binding pocket decreases the affinity by 2-fold. The potential allosteric residues include Ser90, Asn93, Glu94 and W99.The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.

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