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

Abstract

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.

Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines

“…Therefore, compounds 21 were tested at 1 μM in radioligand displacement experiments against four subtypes of adenosine receptors, namely, A 1 , A 2A , A 2B , and A 3 , as previously reported ( Figure S7 and Table S3 , Supporting Information ). 55 In addition, compounds were screened at 10 μM against P2X7R purinergic receptors in an YO-PRO-1 uptake assay 56 ( Figure S8 , Supporting Information ). Performed experiments, however, revealed that synthesized 5,6-dihydro-5-azapurines 21 have little to no affinity/inhibitory activity toward these five purinergic receptors.…”

Optimized synthesis and pharmacological evaluation of HCN channel inhibitor EC18

“…The P2XR assays were performed as previously described by Isaak et al [23] ACKNOWLEDGMENTS Anna Junker thanks the German Research Foundation (DFG) for the financial support (JU 2966/2-1). Anna Junker, Petra Hundehege, Guiscard Seebohm, and Thomas Budde thank the German Research Foundation (DFG) for the financial support (GRK2515/1-1, BU1019/ 16-1).…”