Chemistry:Cebranopadol

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Cebranopadol, also known by its developmental code names TRN-228 and formerly GRT-6005, is an experimental atypical opioid analgesic which is under development for the treatment of various types of pain as well as for treatment of substance-related disorders.[1][2] It is taken orally.[2][3][4]

Side effects of cebranopadol include nausea, vomiting, constipation, somnolence, euphoria, and respiratory depression, among others.[1][5][6] The drug acts as a non-selective opioid receptor agonist, including as a dual μ-opioid receptor and nociceptin receptor full agonist and to a lesser extent as a κ-opioid receptor partial agonist.[7] In relation to its multi-target profile, namely its nociceptin receptor agonism, cebranopadol shows atypical effects and certain potential advantages compared to selective μ-opioid receptor agonists like morphine, such as less misuse potential and respiratory depression.[1][8][7] On the other hand, it has a long half-life in humans and still carries risk of misuse similarly to other opioids.[9][1][10]

Cebranopadol was first described in the patent literature by 2002[11] and in the scientific literature by 2013.[12][13] As of August 2025, it has completed multiple phase 3 clinical trials for treatment of pain.[2][3] According to its developer, a New Drug Application (NDA) is to be submitted in the near future.[14][15] As a dual μ-opioid and nociceptin receptor agonist, cebranopadol is a potential first-in-class medication.[5][1] Cebranopadol is not yet a controlled substance as of 2022.[16] It either has been encountered or could be encountered as a novel opioid recreational designer drug as of 2019.[17]

Medical uses

Cebranopadol remains investigational and is not yet approved for any medical use.[2][3][16]

Side effects

Side effects of cebranopadol include nausea, vomiting, pupil constriction, constipation, somnolence, euphoria, indigestion, and respiratory depression, among others.[1][5][6][18] It has been found to produce less respiratory suppression than other opioid analgesics like oxycodone at equianalgesic doses.[8][5][18]

Misuse potential

Cebranopadol poses misuse potential similarly to other opioid analgesics.[1][10][19] In a misuse liability clinical study however, cebranopadol showed less misuse potential than hydromorphone in recreational opioid users.[1][19] The drug has also shown a low potential for withdrawal symptoms.[5][10]

Pharmacology

Pharmacodynamics

Cebranopadol activities[10][7]
Target Ki (nM) EC50 (nM) Emax (%)
MOR 0.7 1.2 104%
NOP 0.9 13 89%
KOR 2.6 17 67%
DOR 18 110 105%
Notes: Proteins are human. The smaller the value, the more avidly the drug interacts with the site.

Cebranopadol acts as a non-selective opioid receptor agonist, including as a dual μ-opioid receptor (MOR) and nociceptin receptor (NOP) full agonist and to a lesser extent as a κ-opioid receptor partial agonist.[7] It is also a δ-opioid receptor full agonist to a much lesser extent.[7]

The drug shows antinociceptive and antihypertensive effects in a variety of different animal models of pain.[7] It has analgesic ED50 values in animals of 0.5 to 5.6 μg/kg intravenously and 25 μg/kg orally.[7] The drug has been found to be more effective in models of chronic neuropathic pain than acute nociceptive pain compared to selective MOR agonists.[7] Relative to morphine, tolerance to the analgesic effects of cebranopadol has been found to be delayed (26 days versus 11 days for complete tolerance).[7] In addition, unlike morphine, cebranopadol has not been found to affect motor coordination or reduce respiration in animals at doses within or above the dose range for analgesia.[7] As such, it might have improved efficacy and greater tolerability in comparison to existing opioid analgesics.[7]

As an agonist of the KOR, cebranopadol may have the capacity to produce hallucinogenic effects, dysphoria, and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dose range.[17][20]

Pharmacokinetics

The oral absorption of cebranopadol is thought to be complete, while its oral bioavailability is approximately 40%.[5][4] Relatedly, the drug is thought to undergo substantial first-pass metabolism.[4] The time to peak levels of cebranopadol is 4 to 6 hours.[5][4] Cebranopadol shows high permeability into the central nervous system.[1] Its half-value duration (HVD) is 14 to 15 hours, while its terminal elimination half-life is in the range of 62 to 96 hours.[5][4] Cebranopadol with once-daily administration reaches steady-state levels after approximately 2 weeks, with an accumulation ratio of about 2 and a low peak-to-trough fluctuation (PTF) of about 70 to 80%.[5][4]

Chemistry

Cebranopadol is a spiro[cyclohexane-dihydropyrano[3,4-b]indole] derivative of the benzenoid class.[1][21] It is somewhat similar in chemical structure to other indoles with opioid receptor modulator activity like noribogaine and mitragynine.[8][22]

Synthesis

The chemical synthesis of cebranopadol has been described.[23][24]

Analogues

A notable analogue of cebranopadol is lexanopadol (GRT-6006).[25][26]

History

Cebranopadol was originated by Grunenthal and has been subsequently developed by Grunenthal, Park Therapeutics, and Tris Pharma.[2][27] It was first described in a patent in 2002[11] and was first mentioned in the scientific literature by 2013, by which point multiple phase 2 clinical trials had been completed and phase 3 trials were started.[12][13][28][29] Subsequently, several dedicated journal articles on cebranopadol were published in 2014 and 2015.[7][30][31][32]

Society and culture

Names

Cebranopadol is the generic name of the drug and its INN and USAN.[33] It is also known by its developmental code names GRT-6005 (Grünenthal), PRK-101 (Park Therapeutics), and TRN-228 (Tris Pharma).[2][27][3]

Cebranopadol is not yet a controlled substance as of 2022.[16]

Research

Cebranopadol is under development for the treatment of acute pain, back pain, postoperative pain, cancer pain, neuropathic pain, and substance-related disorders.[2][27] As of August 2025, it is in phase 3 trials for acute pain, back pain, and postoperative pain, phase 2 trials for cancer pain and neuropathic pain, and phase 1 trials for substance-related disorders.[2] Phase 3 trials for postoperative pain have been completed and data released.[2][3][14][15] According to Tris Pharma, a New Drug Application (NDA) of cebranopadol would be submitted in 2025.[14][15]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Cebranopadol for the Treatment of Chronic Pain". Curr Pain Headache Rep 27 (10): 615–622. October 2023. doi:10.1007/s11916-023-01148-9. PMID 37556044. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Cebranopadol". AdisInsight. Springer Nature Switzerland AG. 28 August 2025. https://adisinsight.springer.com/drugs/800030045. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Cebranopadol Drug Profile". https://pryzm.ozmosi.com/product/372. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic". Clinical Pharmacokinetics 57 (1): 31–50. January 2018. doi:10.1007/s40262-017-0545-1. PMID 28623508. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 "Opioid MOP receptor agonists in late-stage development for the treatment of postoperative pain". Expert Opin Pharmacother 23 (16): 1831–1843. November 2022. doi:10.1080/14656566.2022.2141566. PMID 36302462. 
  6. ↑ 6.0 6.1 "Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers". Anesthesiology 126 (4): 697–707. April 2017. doi:10.1097/ALN.0000000000001529. PMID 28291085. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 "Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist". The Journal of Pharmacology and Experimental Therapeutics 349 (3): 535–548. June 2014. doi:10.1124/jpet.114.213694. PMID 24713140. 
  8. ↑ 8.0 8.1 8.2 Grundmann, Oliver; Henderson, Allison (28 February 2026). "Indole Alkaloids as Biased Opioid Receptor Modulators". Pharmaceuticals 19 (3): 397. doi:10.3390/ph19030397. ISSN 1424-8247. "An indole derivative itself, cebranopadol is currently in phase 3 clinical trials and did not indicate substantial respiratory depression in animals and lower respiratory depression in healthy human volunteers, which has been attributed to its biased activity at opioid receptors [65].". 
  9. ↑ "Post-surgical pain: evolving drug treatments and challenges". Expert Opinion on Pharmacotherapy 26 (18): 2027–2038. December 2025. doi:10.1080/14656566.2025.2608078. PMID 41416767. 
  10. ↑ 10.0 10.1 10.2 10.3 "NOP-Targeted Nonpeptide Ligands". Handb Exp Pharmacol 254: 37–67. 2019. doi:10.1007/164_2019_213. PMID 31119463. 
  11. ↑ 11.0 11.1 "Spirocyclic cyclohexane compounds". 11 May 2005. https://patents.google.com/patent/US20060004034A1. 
  12. ↑ 12.0 12.1 "Pharmacology of Mixed NOP/Mu Ligands". ACS Symposium Series. 1131. Washington, DC: American Chemical Society. 2013. pp. 369–391. doi:10.1021/bk-2013-1131.ch017. ISBN 978-0-8412-2782-8. https://pubs.acs.org/doi/abs/10.1021/bk-2013-1131.ch017. Retrieved 7 March 2026. "More recently Grunenthal, together with Forest Labs, has taken GRT 6005 into Phase IIb clinical trials. This compound has equal affinity and equal and full efficacy at NOP and mu opiate receptors. Although there is no animal data available in the literature, this compound has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with initial Phase II clinical trials." 
  13. ↑ 13.0 13.1 "CHAPTER 10. Pain Management Companies". Drug Discovery. Cambridge: Royal Society of Chemistry. 2013. pp. 309–325. doi:10.1039/9781849737715-00309. ISBN 978-1-84973-645-9. https://books.rsc.org/books/monograph/1049/chapter-abstract/864570/. Retrieved 7 March 2026. 
  14. ↑ 14.0 14.1 14.2 "Significant Pain Reduction With Cebranopadol Following Bunionectomy". 12 March 2025. https://www.empr.com/news/pain-reduction-with-cebranopadol-following-bunionectomy/. 
  15. ↑ 15.0 15.1 15.2 "Investigational Pain Therapy Cebranopadol Succeeds in Second Phase III Clinical Trial". 6 March 2025. https://www.appliedclinicaltrialsonline.com/view/investigational-pain-therapy-cebranopadol-succeeds-phaseiii-clinical-trial. 
  16. ↑ 16.0 16.1 16.2 "Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review". Cureus 14 (6). June 2022. doi:10.7759/cureus.26000. PMID 35855248. "Since cebranopadol is not yet approved for market release, it has not yet been scheduled by the DEA as a controlled substance.". 
  17. ↑ 17.0 17.1 "Цебранопадол (Cebranopadol)" (in ru). 4 July 2019. https://aipsin.com/newsubstance/108/. 
  18. ↑ 18.0 18.1 "Respiratory and antinociceptive effects of NOP-MOP agonist cebranopadol versus full opioid receptor agonist oxycodone: a comparison in healthy volunteers". Anesthesiology 144 (4): 913–25. December 2025. doi:10.1097/ALN.0000000000005894. PMID 41379941. 
  19. ↑ 19.0 19.1 "Assessment of the Abuse Potential of Cebranopadol in Nondependent Recreational Opioid Users: A Phase 1 Randomized Controlled Study". J Clin Psychopharmacol 39 (1): 46–56. 2019. doi:10.1097/JCP.0000000000000995. PMID 30531478. PMC 6319565. https://pmc.ncbi.nlm.nih.gov/articles/PMC6319565/pdf/jcp-39-46.pdf. 
  20. ↑ "Psychotomimesis mediated by kappa opiate receptors". Science 233 (4765): 774–776. August 1986. doi:10.1126/science.3016896. PMID 3016896. Bibcode: 1986Sci...233..774P. 
  21. ↑ "A Comprehensive Review on Pyranoindole-containing Agents". Curr Med Chem 29 (21): 3667–3683. 2022. doi:10.2174/0929867328666211206111058. PMID 34872472. https://iris.unibas.it/bitstream/11563/157247/1/Catalano%20et%20al.%20Pyranoindoles%20CMC%202022.pdf. "Cebranopadol (4f, Fig. 17) is a spiro[cyclohexane-dihydropyrano[3,4-b]indole], which functions as an opioid analgesic of the benzenoid class [43].". 
  22. ↑ "Narcotics through time: exploring historical origins, synthetic advances, and clinical progress". Future Med Chem 17 (13): 1587–1599. July 2025. doi:10.1080/17568919.2025.2527606. PMID 40621822. "Cebranopadol, a novel analgesic, targets both opioid and nociceptin receptors. It has shown strong efficacy in pain management with a reduced risk of tolerance and abuse, positioning it as a promising alternative for chronic pain treatment [101].". 
  23. ↑ "A diastereoselective synthesis of Cebranopadol, a novel analgesic showing NOP/mu mixed agonism". Scientific Reports 7 (1). May 2017. doi:10.1038/s41598-017-02502-9. PMID 28546566. 
  24. ↑ "Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol". Org Lett 22 (16): 6420–6423. August 2020. doi:10.1021/acs.orglett.0c02234. PMID 32806132. 
  25. ↑ "Lexanopadol". AdisInsight. Springer Nature Switzerland AG. 20 August 2018. https://adisinsight.springer.com/drugs/800034083. 
  26. ↑ "Lexanopadol". https://pubchem.ncbi.nlm.nih.gov/compound/24798598. 
  27. ↑ 27.0 27.1 27.2 "Delving into the Latest Updates on Cebranopadol hemicitrate". Synapse. Patsnap. 27 February 2026. https://synapse.patsnap.com/drug/8a332b3699f94befbdbc0d079363ad6f. 
  28. ↑ "New Chemical Entities Entering Phase III Trials in 2013". Annual Reports in Medicinal Chemistry. 49. Elsevier. 2014. pp. 417–436. doi:10.1016/b978-0-12-800167-7.00026-2. ISBN 978-0-12-800167-7. https://linkinghub.elsevier.com/retrieve/pii/B9780128001677000262. Retrieved 7 March 2026. 
  29. ↑ Clinical trial number NCT01964378 for "CORAL - Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer (CORAL)" at ClinicalTrials.gov
  30. ↑ "Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol". ACS Medicinal Chemistry Letters 5 (8): 857–862. August 2014. doi:10.1021/ml500117c. PMID 25147603. 
  31. ↑ "Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist". British Journal of Anaesthesia 114 (3): 364–366. March 2015. doi:10.1093/bja/aeu332. PMID 25248647. 
  32. ↑ "Cebranopadol: a first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors". Expert Opinion on Investigational Drugs 24 (6): 837–844. June 2015. doi:10.1517/13543784.2015.1036985. PMID 25865744. https://ruj.uj.edu.pl/xmlui/handle/item/102591. 
  33. ↑ "Cebranopadol". https://pubchem.ncbi.nlm.nih.gov/compound/11848225. 



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