Journal Article/Dataset

FZJ-2024-00733

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor

Grohs, L. ; Cheng, L. ; Cönen, S.FZJ* ; Haddad, B. G.FZJ* ; Bülow, A. ; Toklucu, I. ; Ernst, L. ; Körner, J. ; Schmalzing, G. ; Lampert, A. ; Machtens, J.-P.FZJ* ; Hausmann, R. (Corresponding author)

2023
Frontiers Media Lausanne

This record in other databases:      

Please use a persistent id in citations: doi:10.3389/fphar.2023.1120360  doi:10.34734/FZJ-2024-00733

Abstract: Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. Methods: To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. Results: We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 and 76.7 µM, respectively). A weaker inhibition of hP2X1R, hP2X4R, and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, and hP2X7R (IC50 values of 221 µM, 264.1 µM, and ∼900 µM, respectively), calling into question its use as a non-selective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP application or increasing concentrations of the agonist α,β-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results suggest a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains, inhibits the gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R, and hP2X7R. Discussion: Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac, which are rarely reached in the therapeutic range, may play a minor role in analgesia compared to the high-potency cyclooxygenase inhibition but may explain the known side effect of taste disturbances caused by diclofenac.

Note: This study was funded by grants from DeutscheForschungsgemeinschaft (DFG), Germany (grant numbers HA6095/1-1 and HA 6095/1-2) to RH and to J-PM (grant numberMA 7525/2-1, as part of the Research Unit FOR 5046, project P2)and by a grant from the Interdisciplinary Centre for ClinicalResearch within the Faculty of Medicine at the RWTH AachenUniversity (IZKF TN1-1/IA 532001 and TN1-5/IA 532005).

---

Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)

Research Program(s):

1. 5243 - Information Processing in Distributed Systems (POF4-524) (POF4-524)
2. DFG project G:(GEPRIS)426950122 - FOR 5046: Integrative Analyse epithelialer SLC26 Anionentransporter – von der molekularen Struktur zur Pathophysiologie (426950122) (426950122)

Appears in the scientific report 2024

---

Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---