In silico investigation of the selectivity mechanism of A1AR and A2AAR antagonism

Adenosine A1 receptor (A1AR) and adenosine A2A receptor (A2AAR) are AR isoforms that share high homology but play many different roles in terms of regulating arteriolar pressure and urine flow as well as relieving neurodegenerative disorders. Because A1AR and A2AAR have such varied distributions and biological functions, it is critical to distinguish their inhibitory selectivity to minimize unwanted side effects. Thereby, multiple in silico methodologies were used to reveal interactions between key amino acids and selective inhibitors to elucidate the mechanism of selective inhibition towards A1AR and A2AAR. Our results indicated that although A1AR has conserved PHE171 and ASN254, which are also present in A2AAR, namely PHE168 and ASN253, the two isoforms have different binding patterns towards their inhibitors. Generally, A2AAR inhibitors interact with GLU169 via hydrogen bonds, whereas A1AR inhibitors have no corresponding effect. Taken together, our data comprehensively elaborated the selectivity mechanisms of A1AR and A2AAR inhibition, which presents a reasonable guidance, significant for the rational design of selective inhibitors towards A1/A2AAR.