• Conformational changes in the A2AR monitored in a nano-scale membrane disc (SMALP). • Profile of phospholipids in A2AR-SMALP similar to the plasma membrane. • A partially-active conformation of A2AR is supported in a SMALP. • Inverse agonist induced dose-dependent conformational transitions in A2AR-SMALP. • In contrast to inverse agonist, agonist induced only small conformational changes.