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@ARTICLE{Kutzsche:1023080,
      author       = {Kutzsche, Janine and Guzman, Gustavo A. and Willuweit,
                      Antje and Kletke, Olaf and Wollert, Esther and Gering, Ian
                      and Jürgens, Dagmar and Breitkreutz, Jörg and Stark,
                      Holger and Beck-Sickinger, Annette G. and Klöcker, Nikolaj
                      and Hidalgo, Patricia and Willbold, Dieter},
      title        = {{A}n orally available {C}a v 2.2 calcium channel inhibitor
                      for the treatment of neuropathic pain},
      journal      = {British journal of pharmacology},
      volume       = {181},
      number       = {12},
      issn         = {0007-1188},
      address      = {Malden, MA},
      publisher    = {Wiley},
      reportid     = {FZJ-2024-01653},
      pages        = {1734-1756},
      year         = {2024},
      abstract     = {AbstractBackground and Purpose:Neuropathic pain affects up
                      to $10\%$ of the global popula-tion and is caused by an
                      injury or a disease affecting the somatosensory,
                      peripheral,or central nervous system. NP is characterized by
                      chronic, severe and opioid-resistantproperties. Therefore,
                      its clinical management remains very challenging. The
                      N-typevoltage-gated calcium channel, Cav2.2, is a validated
                      target for therapeutic interven-tion in chronic and
                      neuropathic pain. The conotoxin ziconotide (Prialt®) is an
                      FDA-approved drug that blocks Cav2.2 channel but needs to be
                      administered intrathecally.Thus, although being principally
                      efficient, the required application route is very muchin
                      disfavour.Experimental Approach and Key Results:Here, we
                      describe an orally available drugcandidate, RD2, which
                      competes with ziconotide binding to Cav2.2 at
                      nanomolarconcentrations and inhibits Cav2.2 almost
                      completely reversible. Other voltage-gatedcalcium channel
                      subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only
                      at con-centrations higher than 10μM. Data from sciatic
                      inflammatory neuritis rat modeldemonstrated thein vivoproof
                      of concept, as low-dose RD2 (5 mgkg-1) administeredorally
                      alleviated neuropathic pain compared with vehicle controls.
                      High-dose RD2(50 mgkg-1) was necessary to reduce pain
                      sensation in acute thermal responseassessed by the tail
                      flick test.Conclusions and Implications:Taken together,
                      these results demonstrate that RD2has antiallodynic
                      properties. RD2 is orally available, which is the most
                      convenientapplication form for patients and caregivers. The
                      surprising and novel result fromstandard receptor screens
                      opens the room for further optimization into new promis-ing
                      drug candidates, which address an unmet medical need.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {38157867},
      UT           = {WOS:001158587800001},
      doi          = {10.1111/bph.16309},
      url          = {https://juser.fz-juelich.de/record/1023080},
}