Screening of approved drugs regarding their P2X3 receptor activity
The P2X3 receptor (P2X3R), one of the seven members of the ATP-gated P2X receptor family, plays a crucial role in sensory neurotransmission. P2X3 receptor antagonists have been identified as promising drugs to treat chronic cough and are suggested to offer pain relief in chronic pain pain. We have analyzed whether compounds affect P2X3 receptor activity by high-throughput screening (HTS) of the Spectrum Collection of 2000 approved drugs, natural products and bioactive substances (in collaboration with Prof. Michael Schaefer, Rudolf-Boehm-Institut of Pharmacology and Toxicology, University of Leipzig).
Among several hits that markedly inhibited P2X3R activation by ATP, we identified aurintricarboxylic acid (ATA) as a nanomolar-potency antagonist of P2X3 receptor-mediated responses. Two-electrode voltage clamp electrophysiology-based concentration–response analysis and selectivity profiling revealed that ATA strongly inhibits the rP2X1 and rP2X3 receptors.
Molecular docking studies, site-directed mutagenesis and concentration-response analysis revealed that ATA binds to the negative allosteric site of the hP2X3 receptor.
Details on the identification of ATA as a P2X3R antagonist can be found in the publication below. Further hits of the HTS campaign are currently under study.
Obrecht AS, Urban N, Schaefer M, Röse A, Kless A, Meents JE, Lampert A, Abdelrahman A, Müller CE, Schmalzing G, Hausmann R (2019). Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors. Neuropharmacology 2019, 158:107749. https://www.ncbi.nlm.nih.gov/pubmed/31461640
