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@MISC{Grohs:1021437,
      author       = {Grohs, Laura and Cheng, Linhan and Cönen, Saskia and
                      Haddad, Bassam G. and Bülow, Astrid and Toklucu, Idil and
                      Ernst, Lisa and Körner, Jannis and Schmalzing, Günther and
                      Lampert, Angelika and Machtens, Jan-Philipp and Hausmann,
                      Ralf},
      title        = {{D}iclofenac and other non-steroidal anti-inflammatory
                      drugs ({NSAID}s) are competitive antagonists of the human
                      {P}2{X}3 receptor},
      journal      = {Frontiers in pharmacology},
      volume       = {14},
      issn         = {1663-9812},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {FZJ-2024-00733},
      pages        = {1120360},
      year         = {2023},
      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).},
      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.},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5243 - Information Processing in Distributed Systems
                      (POF4-524) / DFG project G:(GEPRIS)426950122 - FOR 5046:
                      Integrative Analyse epithelialer SLC26 Anionentransporter
                      – von der molekularen Struktur zur Pathophysiologie
                      (426950122)},
      pid          = {G:(DE-HGF)POF4-5243 / G:(GEPRIS)426950122},
      typ          = {PUB:(DE-HGF)16 / PUB:(DE-HGF)32},
      pubmed       = {37007008},
      UT           = {WOS:000960653700001},
      doi          = {10.3389/fphar.2023.1120360},
      url          = {https://juser.fz-juelich.de/record/1021437},
}