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
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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