A bifunctional biased mu opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects
Autor: | 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 |
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Přispěvatelé: | 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 |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
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 |
Zdroj: | Pain PAIN PAIN, Elsevier, 2018, 159 (9), pp.1705-1718. ⟨10.1097/j.pain.0000000000001262⟩ |
ISSN: | 0304-3959 1872-6623 |
Popis: | 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. |
Databáze: | OpenAIRE |
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