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024 7 _ |a 10.1111/bph.16309
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024 7 _ |a 1476-5381
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024 7 _ |a 2056-8177
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024 7 _ |a 10.34734/FZJ-2024-01653
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100 1 _ |a Kutzsche, Janine
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245 _ _ |a An orally available Ca v 2.2 calcium channel inhibitor for the treatment of neuropathic pain
260 _ _ |a Malden, MA
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520 _ _ |a 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.
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700 1 _ |a Guzman, Gustavo A.
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700 1 _ |a Willuweit, Antje
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700 1 _ |a Kletke, Olaf
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700 1 _ |a Wollert, Esther
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700 1 _ |a Gering, Ian
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700 1 _ |a Breitkreutz, Jörg
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700 1 _ |a Stark, Holger
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700 1 _ |a Beck-Sickinger, Annette G.
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700 1 _ |a Klöcker, Nikolaj
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700 1 _ |a Hidalgo, Patricia
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700 1 _ |a Willbold, Dieter
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