Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers
| Autor: | Mark J. Gemkow, Jens Nagel, Nikisha Carty, Alexis Laux-Biehlmann, Ioana Neagoe, Thomas M. Zollner, Frederic Machet, Markus Koch, Adam James Davenport, Nico Bräuer, Andrea Rotgeri, Stephen D. Hess, Anne-Marie Coelho, Oliver Fischer, Susan Boyce |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Purinergic P2X Receptor Antagonists
Reproductive disorders Science Endometriosis Gene Expression Bioinformatics Ion channels in the nervous system Article Target validation Cell Line Membrane Potentials Mice Adenosine Triphosphate Nerve Fibers medicine Animals Humans Receptor Sensitization Pharmacology Neurogenic inflammation Multidisciplinary business.industry Drug discovery Pelvic pain Antagonist medicine.disease Rats body regions Disease Models Animal medicine.anatomical_structure Overactive bladder Hyperalgesia Neuroinflammatory Diseases Somatosensory Disorders Medicine Female medicine.symptom business Receptors Purinergic P2X3 |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2045-2322 |
| Popis: | ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers. |
| Databáze: | OpenAIRE |
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