Unveiling the Structure-Activity Relationships at the Orthosteric Binding Site of P2X Ion Channels: The Route to Selectivity

The orthosteric ATP-binding site of the P2X receptors is poorly understood. Only a few compounds were well characterized for their P2X receptor functional activity and subtype selectivity. This study represents the first fully functional character-ization of various ATP derivatives combined with in silico studies to advance the understanding of SARs at the orthosteric binding sites of P2X receptors leading to the identification of 2-chloro-3-trifluoromethylbenzoyl ATP ester as a novel pan-P2X receptor agonist and several subtype-selective P2X receptor agonists. Furthermore, esterification of both hydroxyl functions of ATP using 1-naphthoic acid has led to compound 26 acting as an antagonist at P2X1-4 and P2X2/3 receptors and an agonist at P2X7 receptors. This particular ATP derivative will allow interrogating the P2X7 receptor function while antagonizing all other P2X receptor subtypes and therefore serve as a valuable pharmacological tool in the future.