Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor

Abstract

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.

Keywords:

• alpha2-adrenoceptor
• selectivity
• linker length
• allosteric modulation

Acknowledgments

This work was supported by National Science Foundation of China Grant (81803648, 81470931, 31401188, 31701098, 81803183), Sichuan University Grant (2018SCUH0039, 2016SCU11021, 2016SCU04A08) and Applied Basic Research Program of Sichuan Province Grant (2016JY0027).

Abbreviations

AR, Adrenoceptor; CNS, Central nervous system; [¹²⁵I]-PIC, [¹²⁵I]-paraiodoclonidine.

Disclosure

The authors declare no conflicts of interest in this work.