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NP is characterized by chronic, severe and opioid\u2010resistant properties. Therefore, its clinical management remains very challenging. The N\u2010type voltage\u2010gated calcium channel, Ca<jats:sub>v<\/jats:sub>2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt\u00ae) is an FDA\u2010approved drug that blocks Ca<jats:sub>v<\/jats:sub>2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach and Key Results<\/jats:title><jats:p>Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Ca<jats:sub>v<\/jats:sub>2.2 at nanomolar concentrations and inhibits Ca<jats:sub>v<\/jats:sub>2.2 almost completely reversible. Other voltage\u2010gated calcium channel subtypes, like Ca<jats:sub>v<\/jats:sub>1.2 and Ca<jats:sub>v<\/jats:sub>3.2, were affected by RD2 only at concentrations higher than 10\u00a0\u03bcM. Data from sciatic inflammatory neuritis rat model demonstrated the <jats:italic>in vivo<\/jats:italic> proof of concept, as low\u2010dose RD2 (5\u00a0mg\u00b7kg<jats:sup>\u20101<\/jats:sup>) administered orally alleviated neuropathic pain compared with vehicle controls. High\u2010dose RD2 (50\u2009mg\u00b7kg<jats:sup>\u20101<\/jats:sup>) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16309","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T23:34:30Z","timestamp":1703892870000},"page":"1734-1756","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["An orally available Ca<sub>v<\/sub>2.2\u00a0calcium channel inhibitor for the treatment of neuropathic pain"],"prefix":"10.1111","volume":"181","author":[{"given":"Janine","family":"Kutzsche","sequence":"first","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo A.","family":"Guzman","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Willuweit","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience and Medicine, Medical Imaging Physics Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Kletke","sequence":"additional","affiliation":[{"name":"Institute of Neuro\u2010 und Sensory Physiology, Medical Faculty Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Wollert","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Gering","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"J\u00fcrgens","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Breitkreutz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-1710","authenticated-orcid":false,"given":"Holger","family":"Stark","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical and Medicinal Chemistry Heinrich\u2010Heine\u2010University D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette G.","family":"Beck\u2010Sickinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Universit\u00e4t Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaj","family":"Kl\u00f6cker","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutics and Biopharmaceutics Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Hidalgo","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 1, Molecular and Cellular Physiology Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Willbold","sequence":"additional","affiliation":[{"name":"Institute of Biological Information Processing 7, Structural Biochemistry Forschungszentrum J\u00fclich GmbH  J\u00fclich Germany"},{"name":"Institut f\u00fcr Physikalische Biologie Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.011"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15539"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","unstructured":"Attali B. 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