Identification of Novel Adenosine A_2A Receptor Antagonists by Virtual Screening

Abstract

Virtual screening was performed against experimentally enabled homology models of the adenosine A_2A receptor, identifying a diverse range of ligand efficient antagonists (hit rate 9%). By use of ligand docking and Biophysical Mapping (BPM), hits <b>1</b> and <b>5</b> were optimized to potent and selective lead molecules (<b>11</b>–<b>13</b> from <b>5</b>, p<i>K</i>_I = 7.5–8.5, 13- to >100-fold selective versus adenosine A₁; <b>14</b>–<b>16</b> from <b>1</b>, p<i>K</i>_I = 7.9–9.0, 19- to 59-fold selective)