An orally available Ca v 2.2 calcium channel inhibitor for the treatment of neuropathic pain.

Autor: Kutzsche J; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany., Guzman GA; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany., Willuweit A; Institute of Neuroscience and Medicine, Medical Imaging Physics, Forschungszentrum Jülich GmbH, Jülich, Germany., Kletke O; Institute of Neuro- und Sensory Physiology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Wollert E; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany., Gering I; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany., Jürgens D; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany., Breitkreutz J; Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Stark H; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Beck-Sickinger AG; Institute of Biochemistry, Universität Leipzig, Leipzig, Germany., Klöcker N; Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany., Hidalgo P; Institute of Biological Information Processing 1, Molecular and Cellular Physiology, Forschungszentrum Jülich GmbH, Jülich, Germany., Willbold D; Institute of Biological Information Processing 7, Structural Biochemistry, Forschungszentrum Jülich GmbH, Jülich, Germany.; Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Jun; Vol. 181 (12), pp. 1734-1756. Date of Electronic Publication: 2024 Feb 07.
DOI: 10.1111/bph.16309
Abstrakt: Background and Purpose: Neuropathic pain affects up to 10% of the global population 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-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Ca v 2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Ca v 2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour.
Experimental Approach and Key Results: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Ca v 2.2 at nanomolar concentrations and inhibits Ca v 2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Ca v 1.2 and Ca v 3.2, were affected by RD2 only at concentrations higher than 10 μM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg -1 ) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg -1 ) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test.
Conclusions and Implications: 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.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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