Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist
| Autor: | Thomas M. Tzschentke, Michael Gautrois, Wolfgang P. Schröder, Stefan Schunk, Werner Englberger, Horst Beier, Thomas Christoph, Klaus Schiene, Jean De Vry, Thomas Koch, Babette Kögel, Ulrich Jahnel, Klaus Linz, Stefanie Frosch |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Indoles medicine.drug_class NOP Analgesic Pain Bone Neoplasms CHO Cells (+)-Naloxone Pharmacology Rats Sprague-Dawley Polyneuropathies Radioligand Assay Cricetulus Opioid receptor Cricetinae medicine Animals Spiro Compounds Rats Wistar Behavior Animal Chemistry Cebranopadol Cell Membrane Receptor antagonist Arthritis Experimental Rats Analgesics Opioid Nociceptin receptor Opioid Peptides Opioid Rotarod Performance Test Receptors Opioid Molecular Medicine Female Protein Binding medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 349:535-548 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5-5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol's duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|