A bifunctional biased mu opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects
| العنوان: | A bifunctional biased mu opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects |
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| المؤلفون: | Steven Ballet, Armand Drieu la Rochelle, Pieter Mampuys, Valérie Utard, Frédéric Bihel, Séverine Schneider, Mariana Spetea, François Daubeuf, Karel Guillemyn, Tom Willemse, Maria Dumitrascuta, Nelly Frossard, Bert U. W. Maes, Raphaëlle Quillet, Charlotte Martin, Frédéric Simonin |
| المساهمون: | Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), CHU Toulouse [Toulouse], Laboratoire d'Innovation Thérapeutique (LIT), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC), department of chemistry, University of Antwerp (UA), Inflammation et environnement dans l'asthme, Université Louis Pasteur - Strasbourg I-Faculté de Pharmacie, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculty of Sciences and Bioengineering Sciences, Chemistry, WE Academic Unit |
| المصدر: | Pain PAIN PAIN, Elsevier, 2018, 159 (9), pp.1705-1718. ⟨10.1097/j.pain.0000000000001262⟩ |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, Pain Threshold, Receptors, Neuropeptide, 0301 basic medicine, Agonist, medicine.drug_class, Physical dependence, [SDV]Life Sciences [q-bio], Analgesic, Receptors, Opioid, mu, Pain, Neuropeptide FF receptor, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Motor Activity, Pharmacology, opioid receptors, Mice, 03 medical and health sciences, RF-amide peptides, 0302 clinical medicine, Opioid analgesia, NPFF receptors, Analgesic tolerance, Animals, Humans, Medicine, Neuropeptide FF, Opioid-induced hyperalgesia, ComputingMilieux_MISCELLANEOUS, business.industry, Sciences du Vivant [q-bio]/Biotechnologies, 3. Good health, Analgesics, Opioid, Chemistry, HEK293 Cells, 030104 developmental biology, Anesthesiology and Pain Medicine, Neurology, Opioid, Hyperalgesia, Neurology (clinical), Human medicine, medicine.symptom, Respiratory Insufficiency, business, Oxycodone, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | Opioid analgesics, such as morphine, oxycodone and fentanyl, are the cornerstones for treating moderate to severe pain. However, upon chronic administration, their efficiency is limited by prominent side effects such as analgesic tolerance and dependence liability. Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are recognized as an important pronociceptive system involved in opioid-induced hyperalgesia and analgesic tolerance. Herein, we report the design of multitarget peptidomimetic compounds that show high affinity binding to the mu opioid receptor (MOPr) and NPFFRs. In vitro characterization of these compounds led to identification of KGFF03 and KGFF09 as G protein-biased MOPr agonists with full agonist or antagonist activity at NPFFRs, respectively. In agreement with their biased MOPr agonism, KGFF03/09 showed reduced respiratory depression in mice, as compared to the unbiased parent opioid agonist KGOP01. Chronic subcutaneous administration of KGOP01 and KGFF03 in mice rapidly induced hyperalgesia and analgesic tolerance, effects that were not observed upon chronic treatment with KGFF09. This favorable profile was further confirmed in a model of persistent inflammatory pain. In addition, we showed that KGFF09 induced less physical dependence compared to KGOP01 and KGFF03. Altogether, our data establish that combining, within a single molecule, the G protein-biased MOPr agonism and NPFFR antagonism, have beneficial effects on both acute and chronic side effects of conventional opioid analgesics. This strategy can lead to the development of novel and potent antinociceptive drugs with limited side effects upon acute and chronic administration. |
| وصف الملف: | |
| اللغة: | English |
| تدمد: | 0304-3959 1872-6623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c453b72695ed1438ea7ad7e1b1b004b1 https://hdl.handle.net/10067/1506770151162165141 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c453b72695ed1438ea7ad7e1b1b004b1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 03043959 18726623 |
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