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Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain

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العنوان: Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain
المؤلفون: Giacomo Rossino, Annamaria Marra, Roberta Listro, Marco Peviani, Elena Poggio, Daniela Curti, Giorgia Pellavio, Umberto Laforenza, Giulio Dondio, Dirk Schepmann, Bernhard Wünsch, Martina Bedeschi, Noemi Marino, Anna Tesei, Hee-Jin Ha, Young-Ho Kim, Jihyae Ann, Jeewoo Lee, Pasquale Linciano, Marcello Di Giacomo, Daniela Rossi, Simona Collina
المصدر: Pharmaceuticals, Vol 16, Iss 7, p 962 (2023)
بيانات النشر: MDPI AG, 2023.
سنة النشر: 2023
المجموعة: LCC:Medicine
LCC:Pharmacy and materia medica
مصطلحات موضوعية: sigma 1 receptor antagonist, neuropathic pain, antinociceptive activity, zebrafish model, Medicine, Pharmacy and materia medica, RS1-441
الوصف: Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world’s population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. (R/S)-RC-752 emerged as the most interesting compound for S1R affinity (Ki S1R = 6.2 ± 0.9) and functional antagonist activity. Furthermore, it showed no cytotoxic effect in two normal human cell lines or in an in vivo zebrafish model and was stable after incubation in mouse plasma. (R/S)-RC-752 was then evaluated in two animal models of NP: the formalin test and the spinal nerve ligation model. The results clearly demonstrated that compound (R/S)-RC-752 effectively alleviated pain in both animal models, thus providing the proof of concept of its efficacy as an antinociceptive agent.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1424-8247
Relation: https://www.mdpi.com/1424-8247/16/7/962; https://doaj.org/toc/1424-8247
DOI: 10.3390/ph16070962
URL الوصول: https://doaj.org/article/35d4e6301ce4448da02e9dbd77693350
رقم الأكسشن: edsdoj.35d4e6301ce4448da02e9dbd77693350
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:14248247
DOI:10.3390/ph16070962