Cebranopadol

Cebranopadol (developmental code GRT-6005) is an opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states.[1][2][3] As of November 2014, it is in phase III clinical trials.

Cebranopadol
Clinical data
Routes of
administration		Oral
ATC code
  • None
Pharmacokinetic data
Elimination half-life~4.5 hours
Identifiers
IUPAC name
  • (1r,4r)-6’-Fluoro-N,N-dimethyl-4-phenyl-4’,9’-dihydro-3’H-spiro[cyclohexane-1,1’-pyrano[3,4-b]indol]-4-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC24H27FN2O
Molar mass378.491 g·mol−1
3D model (JSmol)
SMILES
  • CN(C)[C@@]1(c2ccccc2)CC[C@@]2(CC1)OCCc1c2[nH]c2ccc(F)cc12
InChI
  • InChI=1S/C24H27FN2O/c1-27(2)23(17-6-4-3-5-7-17)11-13-24(14-12-23)22-19(10-15-28-24)20-16-18(25)8-9-21(20)26-22/h3-9,16,26H,10-15H2,1-2H3/t23-,24-
  • Key:CSMVOZKEWSOFER-RQNOJGIXSA-N

Cebranopadol is unique in its mechanism of action as an opioid, binding to and activating all four of the opioid receptors; it acts as a full agonist of the μ-opioid receptor (Ki = 0.7 nM; EC50 = 1.2 nM; IA = 104%), and δ-opioid receptor (Ki = 18 nM; EC50 = 110 nM; IA = 105%), and as a partial agonist of the nociceptin receptor (Ki = 0.9 nM; EC50 = 13.0 nM; IA = 89%) and κ-opioid receptor (Ki = 2.6 nM; EC50 = 17 nM; IA = 67%).[1] The EC50 values of 0.5–5.6 µg/kg when introduced intravenously and 25.1 µg/kg after oral administration.[4]

Cebranopadol shows highly potent and effective antinociceptive and antihypertensive effects in a variety of different animal models of pain.[1] Notably, it has also been found to be more potent in models of chronic neuropathic pain than acute nociceptive pain compared to selective μ-opioid receptor agonists.[1] Relative to morphine, tolerance to the analgesic effects of cebranopadol has been found to be delayed (26 days versus 11 days for complete tolerance).[1] In addition, unlike morphine, cebranopadol has not been found to affect motor coordination or reduce respiration in animals at doses in or over the dosage range for analgesia.[1] As such, it may have improved and prolonged efficaciousness and greater tolerability in comparison to currently available opioid analgesics.[1]

As an agonist of the κ-opioid receptor, cebranopadol may have the capacity to produce psychotomimetic effects, dysphoria, and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dosage range, but would likely reduce the occurrence of patients taking more than their prescribed dose.[5]

See also

References
  1. Linz K, Christoph T, Tzschentke TM, et al. (June 2014). "Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist". J. Pharmacol. Exp. Ther. 349 (3): 535–48. doi:10.1124/jpet.114.213694. PMID 24713140. S2CID 6942770.
  2. Schunk S, Linz K, Hinze C, et al. (August 2014). "Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol". ACS Med Chem Lett. 5 (8): 857–62. doi:10.1021/ml500117c. PMC 4137374. PMID 25147603.
  3. Lambert DG, Bird MF, Rowbotham DJ (September 2014). "Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist". Br J Anaesth. 114 (3): 364–6. doi:10.1093/bja/aeu332. PMID 25248647.
  4. Linz, K.; Christoph, T.; Tzschentke, T. M.; Koch, T.; Schiene, K.; Gautrois, M.; Schroder, W.; Kogel, B. Y.; Beier, H.; Englberger, W.; Schunk, S.; De Vry, J.; Jahnel, U.; Frosch, S. (Jun 2014). "Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist". Journal of Pharmacology and Experimental Therapeutics. 349 (3): 535–48. doi:10.1124/jpet.114.213694. PMID 24713140. S2CID 6942770.
  5. Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). "Psychotomimesis mediated by kappa opiate receptors". Science. 233 (4765): 774–6. Bibcode:1986Sci...233..774P. doi:10.1126/science.3016896. PMID 3016896. S2CID 37512800.
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