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Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist.
J Pharmacol Exp Ther. 2014 Jun; 349(3):535-48.JP

Abstract

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.

Authors+Show Affiliations

Departments of Preclinical Drug Safety (K.L.), Global Preclinical Drug Development (S.F.), Global Preclinical Research and Development (U.J.), Pain Pharmacology (T.C., T.M.T., K.S., B.Y.K., J.D.V.), Molecular Pharmacology (T.K., W.E.), Translational Science (W.S.), Pharmacokinetics (M.G., H.B.), and Medicinal Chemistry (S.S.), Grünenthal GmbH, Aachen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24713140

Citation

Linz, Klaus, et al. "Cebranopadol: a Novel Potent Analgesic Nociceptin/orphanin FQ Peptide and Opioid Receptor Agonist." The Journal of Pharmacology and Experimental Therapeutics, vol. 349, no. 3, 2014, pp. 535-48.
Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535-48.
Linz, K., Christoph, T., Tzschentke, T. M., Koch, T., Schiene, K., Gautrois, M., Schröder, W., Kögel, B. Y., Beier, H., Englberger, W., Schunk, S., De Vry, J., Jahnel, U., & Frosch, S. (2014). Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. The Journal of Pharmacology and Experimental Therapeutics, 349(3), 535-48. https://doi.org/10.1124/jpet.114.213694
Linz K, et al. Cebranopadol: a Novel Potent Analgesic Nociceptin/orphanin FQ Peptide and Opioid Receptor Agonist. J Pharmacol Exp Ther. 2014;349(3):535-48. PubMed PMID: 24713140.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. AU - Linz,Klaus, AU - Christoph,Thomas, AU - Tzschentke,Thomas M, AU - Koch,Thomas, AU - Schiene,Klaus, AU - Gautrois,Michael, AU - Schröder,Wolfgang, AU - Kögel,Babette Y, AU - Beier,Horst, AU - Englberger,Werner, AU - Schunk,Stefan, AU - De Vry,Jean, AU - Jahnel,Ulrich, AU - Frosch,Stefanie, Y1 - 2014/04/08/ PY - 2014/4/10/entrez PY - 2014/4/10/pubmed PY - 2014/7/7/medline SP - 535 EP - 48 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 349 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/24713140/Cebranopadol:_a_novel_potent_analgesic_nociceptin/orphanin_FQ_peptide_and_opioid_receptor_agonist_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=24713140 DB - PRIME DP - Unbound Medicine ER -