investigation of the selectivity mechanism of AAR and AAR antagonism

Adenosine A 1 receptor (A 1 AR) and adenosine A 2A receptor (A 2A AR) 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 A 1 AR and A 2A AR 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 A 1 AR and A 2A AR. Our results indicated that although A 1 AR has conserved PHE171 and ASN254, which are also present in A 2A AR, namely PHE168 and ASN253, the two isoforms have different binding patterns towards their inhibitors. Generally, A 2A AR inhibitors interact with GLU169 via hydrogen bonds, whereas A 1 AR inhibitors have no corresponding effect. Taken together, our data comprehensively elaborated the selectivity mechanisms of A 1 AR and A 2A AR inhibition, which presents a reasonable guidance, significant for the rational design of selective inhibitors towards A 1 /A 2A AR. Adenosine A 1 receptor (A 1 AR) and adenosine A 2A receptor (A 2A AR) 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.