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@ARTICLE{Schmidt:857533,
      author       = {Schmidt, Axel and Rossetti, Giulia and Joussen, Sylvia and
                      Gründer, Stefan},
      title        = {{D}iminazene {I}s a {S}low {P}ore {B}locker of
                      {A}cid-{S}ensing {I}on {C}hannel 1a ({ASIC}1a)},
      journal      = {Molecular pharmacology},
      volume       = {92},
      number       = {6},
      issn         = {1521-0111},
      address      = {Bethesda, Md.},
      publisher    = {ASPET},
      reportid     = {FZJ-2018-06524},
      pages        = {665 - 675},
      year         = {2017},
      abstract     = {Acid-sensing ion channels (ASICs) are neuronal receptors
                      for extracellular protons. They contribute to the excitatory
                      postsynaptic current and to the detection of painful
                      acidosis. Moreover, they are activated during peripheral
                      inflammation and acidosis associated with various neuronal
                      disorders, such as stroke and neuroinflammation, rendering
                      them interesting drug targets. Diminazene aceturate is a
                      small-molecule inhibitor of ASICs with a reported apparent
                      affinity in the low micromolar range, making it an
                      interesting lead compound. It was reported that diminazene
                      accelerates desensitization of ASICs, which was, however,
                      not explained mechanistically. Furthermore, a binding site
                      in a groove of the extracellular domain was proposed but not
                      experimentally verified. In this study, we revisited the
                      mechanism of inhibition by diminazene and its binding site
                      on ASIC1a, the ASIC subunit with the greatest importance in
                      the central nervous system. We show that diminazene slowly
                      blocks ASIC1a, leading to the apparent acceleration of
                      desensitization and underestimating its potency; we show
                      that diminazene indeed has a submicromolar potency at ASIC1a
                      (IC50 0.3 μM). Moreover, we show that the inhibition is
                      voltage-dependent and competes with that by amiloride, a
                      pore blocker of ASICs. Finally, we identify by molecular
                      docking a binding site in the ion pore that we confirm by
                      site-directed mutagenesis. In summary, our results show that
                      diminazene blocks ASIC1a by a slow open-channel block and
                      suggest that diminazene is an interesting lead compound for
                      high-affinity blockers of ASICs.},
      cin          = {IAS-5 / JSC},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)JSC-20090406},
      pnm          = {574 - Theory, modelling and simulation (POF3-574) / 511 -
                      Computational Science and Mathematical Methods (POF3-511)},
      pid          = {G:(DE-HGF)POF3-574 / G:(DE-HGF)POF3-511},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29025967},
      UT           = {WOS:000415985000007},
      doi          = {10.1124/mol.117.110064},
      url          = {https://juser.fz-juelich.de/record/857533},
}