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 characterization 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.