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 (p Ki=− 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