Advertisement

Cebranopadol: A Novel First-in-Class Potent Analgesic Acting via NOP and Opioid Receptors

  • Thomas M. TzschentkeEmail author
  • Klaus Linz
  • Thomas Koch
  • Thomas Christoph
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 254)

Abstract

Cebranopadol is a novel first-in-class analgesic with highly potent agonistic activity at nociceptin/orphanin FQ peptide (NOP) and opioid receptors. It is highly potent and efficacious across a broad range of preclinical pain models. Its side effect profile is better compared to typical opioids. Mechanistic studies have shown that cebranopadol’s activity at NOP receptors contributes to its anti-hyperalgesic effects while ameliorating some of its opioid-type side effects, including respiratory depression and abuse potential. Phase II of clinical development has been completed, demonstrating efficacy and good tolerability in acute and chronic pain conditions.

This article focusses on reviewing data on the preclinical in vitro and in vivo pharmacology, safety, and tolerability, as well as clinical trials with cebranopadol.

Keywords

Cancer pain Chronic low back pain Diabetic peripheral neuropathy Nociceptin/orphanin FQ Postoperative pain Respiratory depression 

Notes

Acknowledgments

Thanks are given to Stefanie Frosch and Marielle Eerdekens for careful revision of the manuscript.

References

  1. Asth L, Ruzza C, Malfacini D et al (2016) Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. Neuropharmacology 105:434–442PubMedPubMedCentralGoogle Scholar
  2. Benredjem B, Dallaire P, Pineyro G (2017) Analyzing biased responses of GPCR ligands. Curr Opin Pharmacol 32:71–76PubMedGoogle Scholar
  3. Bird MF, Lambert DG (2015) Simultaneous targeting of multiple opioid receptor types. Curr Opin Support Palliat Care 9:98–102PubMedGoogle Scholar
  4. Bohn LM, Lefkowitz RJ, Gainetdinov RR et al (1999) Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286:2495–2498PubMedGoogle Scholar
  5. Bohn LM, Gainetdinov RR, Lin FT et al (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408:720–723PubMedGoogle Scholar
  6. Bologna Z, Teoh JP, Bayoumi AS et al (2017) Biased G protein-coupled receptor signaling: new player in modulating physiology and pathology. Biomol Ther 25:12–25Google Scholar
  7. Calo’ G, Lambert DG (2018) Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic. Br J Anaesth 121:1105–1114Google Scholar
  8. Camarda V, Fischetti C, Anzellotti N et al (2009) Pharmacological profile of NOP receptors coupled with calcium signaling via the chimeric protein G alpha qi5. Naunyn Schmiedeberg’s Arch Pharmacol 379:599–607Google Scholar
  9. Chang SD, Brieaddy LE, Harvey JD et al (2015a) Novel synthesis and pharmacological characterization of NOP receptor agonist 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198). ACS Chem Neurosci 6:1956–1964PubMedPubMedCentralGoogle Scholar
  10. Chang SD, Mascarella SW, Spangler SM et al (2015b) Quantitative signaling and structure-activity analyses demonstrate functional selectivity at the nociceptin/orphanin FQ Ooioid receptor. Mol Pharmacol 88:502–511PubMedGoogle Scholar
  11. Charlton SJ, Vauquelin G (2010) Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays. Br J Pharmacol 161:1250–1265PubMedGoogle Scholar
  12. Christoph T, Kögel B, Strassburger W et al (2007) Tramadol has a better potency ratio relative to morphine in neuropathic than in nociceptive pain models. Drugs R D 8:51–57PubMedGoogle Scholar
  13. Christoph A, Eerdekens MH, Kok M et al (2017) Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain 158:1813–1824PubMedPubMedCentralGoogle Scholar
  14. Christoph T, Raffa R, De Vry J et al (2018) Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model. Pharmacol Res Perspect.  https://doi.org/10.1002/prp2.444 Google Scholar
  15. Chung S, Pohl S, Zeng J et al (2006) Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 318:262–267Google Scholar
  16. Ciccocioppo R, Angeletti S, Sanna PP et al (2000) Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol 404:153–159PubMedPubMedCentralGoogle Scholar
  17. Comer SD, Ashworth JB, Sullivan MA et al (2009) Relationship between rate of infusion and reinforcing strength of oxycodone in humans. J Opioid Manag 5:203–212PubMedGoogle Scholar
  18. Courteix C, Coudoré-Civiale MA, Privat AM et al (2004) Evidence for an exclusive antinociceptive effect of nociceptin/orphanin FQ, an endogenous ligand for the ORL1 receptor, in two animal models of neuropathic pain. Pain 110:236–245PubMedGoogle Scholar
  19. Cremeans CM, Gruley E, Kyle DJ et al (2012) Roles of μ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther 343:72–81PubMedGoogle Scholar
  20. de Guglielmo G, Matzeu A, Kononoff J et al (2017) Cebranopadol blocks the escalation of cocaine intake and conditioned reinstatement of cocaine seeking in rats. J Pharmacol Exp Ther 362:378–384PubMedPubMedCentralGoogle Scholar
  21. Dahan A, Yassen A, Bijl H et al (2005) Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 94:825–834PubMedGoogle Scholar
  22. Dahan A, Boom M, Sarton E et al (2017) Respiratory effects of the nociceptin/orphanin FQ peptide and opioid receptor agonist, cebranopadol, in healthy human volunteers. Anesthesiology 126:697–707Google Scholar
  23. Ding H, Czoty PW, Kiguchi N et al (2016) A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci 113:E5511–E5518PubMedGoogle Scholar
  24. Ding H, Kiguchi N, Yasuda D et al (2018) A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates. Sci Transl Med 10:eaar3483Google Scholar
  25. Eerdekens M, Koch ED, Kok M et al (2016) Cebranopadol, a novel first-in-class analgesic: efficacy, safety, tolerability in patients with pain due to diabetic peripheral neuropathy. Postgrad Med 128(Suppl 2):25Google Scholar
  26. Eerdekens MH, Kapanadze S, Koch ED et al (2018) Cancer related chronic pain: investigation of the novel analgesic drug candidate cebranopadol in a randomized, double blind, noninferiority trial. Eur J Pain.  https://doi.org/10.1002/ejp.1331 PubMedGoogle Scholar
  27. Fantinati A, Bianco S, Guerrini R et al (2017) A diastereoselective synthesis of cebranopadol, a novel analgesic showing NOP/mu mixed agonism. Sci Rep 7:2416PubMedGoogle Scholar
  28. Göhler K, Sokolowska M, Schoedel K et al (2018) Assessment of the abuse potential of cebranopadol in non-dependent recreational opioid users: a phase 1 randomized controlled study. J Clin Psychopharmacol.  https://doi.org/10.1097/JCP.0000000000000995 PubMedGoogle Scholar
  29. Higgins GA, Grottick AJ, Ballard TM et al (2001) Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function. Neuropharmacology 41:97–107PubMedGoogle Scholar
  30. Hu E, Calò G, Guerrini R et al (2010) Long-lasting antinociceptive spinal effects in primates of the novel nociceptin/orphanin FQ receptor agonist UFP-112. Pain 148:107–113Google Scholar
  31. Journigan VB, Polgar WE, Khroyan TV et al (2014) Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II. Bioorg Med Chem 22:2508–2516PubMedPubMedCentralGoogle Scholar
  32. Khroyan TV, Polgar WE, Cami-Kobeci G et al (2011) The first universal opioid ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward. J Pharmacol Exp Ther 336:952–961PubMedPubMedCentralGoogle Scholar
  33. Khroyan TV, Cippitelli A, Toll N et al (2017) In vitro and in vivo profile of PPL-101 and PPL-103: mixed opioid partial agonist analgesics with low abuse potential. Front Psych 8:52Google Scholar
  34. Kleideiter E, Piana C, Wang S et al (2018) Clinical pharmacokinetic characteristics of cebranopadol, a novel first-in-class analgesic. Clin Pharmacokinet 57:31–50. Erratum in: Clin Pharmacokinet 57:1057–1058PubMedGoogle Scholar
  35. Ko MC, Naughton NN (2009) Antinociceptive effects of nociceptin/orphanin FQ administered intrathecally in monkeys. J Pain 10:509–516PubMedGoogle Scholar
  36. Kotlińska J, Suder P, Legowska A et al (2000) OrphaninFQ/nociceptin inhibits morphine withdrawal. Life Sci 66:PL119–PL123PubMedGoogle Scholar
  37. Kotlinska J, Wichmann J, Rafalski P et al (2003) Non-peptidergic OP4 receptor agonist inhibits morphine antinociception but does not influence morphine dependence. Neuroreport 14:601–604PubMedGoogle Scholar
  38. Lambert DG, Bird MF, Rowbotham DJ (2015) Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth 114:364–366Google Scholar
  39. Linz K, Christoph T, Tzschentke TM et al (2014) Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349:535–548Google Scholar
  40. Linz K, Schröder W, Frosch S et al (2017) Opioid-type respiratory depressant side effects of cebranopadol in rats are limited by its nociceptin/orphanin FQ peptide receptor agonist activity. Anesthesiology 126:708–715PubMedGoogle Scholar
  41. Lutfy K, Hossain SM, Khaliq I et al (2001) Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br J Pharmacol 134:529–534PubMedPubMedCentralGoogle Scholar
  42. Malfacini D, Ambrosio C, Gro’ MC et al (2015) Pharmacological profile of nociceptin/orphanin FQ receptors interacting with G-proteins and β-arrestins 2. PLoS One 10:e0132865PubMedPubMedCentralGoogle Scholar
  43. Meert TF, Vermeirsch HA (2005) A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav 80:309–326PubMedGoogle Scholar
  44. Micheli L, Lucarini E, Corti F et al (2018) Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: are astrocytes the crossroad? Eur J Pharmacol 823:79–86PubMedPubMedCentralGoogle Scholar
  45. Murphy NP, Lee Y, Maidment NT (1999) Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res 832:168–170Google Scholar
  46. Piana C, Wang S, Bursi R (2016) A novel model-based methodology for the evaluation of abuse potential. https://www.page-meeting.org/pdf_assets/2662-Poster_PAGE_2016_final.pdf. Accessed 30 Aug 2018
  47. Podlesnik CA, Ko MC, Winger G et al (2011) The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology 213:53–60Google Scholar
  48. Raehal KM, Walker JK, Bohn LM (2005) Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther 314:1195–1201PubMedGoogle Scholar
  49. Raffa RB, Burdge G, Gambrah J et al (2017) Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. J Clin Pharm Ther 42:8–17PubMedGoogle Scholar
  50. Reiss D, Wichmann J, Tekeshima H et al (2008) Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine. Eur J Pharmacol 579:141–148PubMedGoogle Scholar
  51. Rizzi A, Malfacini D, Cerlesi MC et al (2014) In vitro and in vivo pharmacological characterization of nociceptin/orphanin FQ tetrabranched derivatives. Br J Pharmacol 171:4138–4153PubMedGoogle Scholar
  52. Rizzi A, Cerlesi MC, Ruzza C et al (2016) Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist. Pharmacol Res Perspect 4:e00247PubMedGoogle Scholar
  53. Rizzi A, Ruzza C, Bianco S et al (2017) Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test. Peptides 94:71–77PubMedGoogle Scholar
  54. Rutten K, De Vry J, Bruckmann W et al (2010) Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate- and psychostimulant-induced conditioned place preference in rats. Eur J Pharmacol 645:119–126PubMedPubMedCentralGoogle Scholar
  55. Rutten K, De Vry J, Bruckmann W et al (2011) Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats. Drug Alcohol Depend 114:253–256PubMedPubMedCentralGoogle Scholar
  56. Rutten K, Schröder W, Christoph T et al (2018) Selectivity profiling of NOP, MOP, DOP and KOP receptor antagonists in the rat spinal nerve ligation model of mononeuropathic pain. Eur J Pharmacol 827:41–48PubMedGoogle Scholar
  57. Ruzza C, Rizzi A, Malfacini D et al (2014) Pharmacological characterization of tachykinin tetrabranched derivatives. Br J Pharmacol 171:4125–4137PubMedGoogle Scholar
  58. Ruzza C, Holanda VA, Gavioli EC et al (2018) NOP agonist action of cebranopadol counteracts its liability to promote physical dependence. Peptides 112:101–105PubMedPubMedCentralGoogle Scholar
  59. Sałat K, Jakubowska A, Kulig K (2015) Cebranopadol: a first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors. Expert Opin Investig Drugs 24:837–844PubMedGoogle Scholar
  60. Salat K, Furgala A, Salat R (2018) Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain. Inflammopharmacology 26:361–374PubMedGoogle Scholar
  61. Schiene K, De Vry J, Tzschentke TM (2011) Antinociceptive and antihyperalgesic effects of tapentadol in animal models of inflammatory pain. J Pharmacol Exp Ther 339:537–544PubMedGoogle Scholar
  62. Schiene K, Schröder W, Linz K et al (2018a) Inhibition of experimental visceral pain in rodents by cebranopadol. Behav Pharmacol.  https://doi.org/10.1097/FBP.0000000000000420 PubMedGoogle Scholar
  63. Schiene K, Schröder W, Linz K et al (2018b) Nociceptin/orphanin FQ opioid peptide (NOP) receptor and micro-opioid peptide (MOP) receptors both contribute to the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain. Eur J Pharmacol 832:90–95PubMedGoogle Scholar
  64. Scholz A, Bothmer J, Kok M et al (2018) Cebranopadol: a novel, first-in-class, strong analgesic: results from a randomized phase IIa clinical trial in postoperative acute pain. Pain Physician 21:E193–E206Google Scholar
  65. Schröder W, Lambert DG, Ko MC et al (2014) Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol 171:3777–3800PubMedPubMedCentralGoogle Scholar
  66. Schunk S, Linz K, Hinze C et al (2014) Discovery of a potent analgesic NOP and opioid receptor agonist: cebranopadol. ACS Med Chem Lett 5:857–862PubMedPubMedCentralGoogle Scholar
  67. Shen Q, Deng Y, Ciccocioppo R et al (2017) Cebranopadol, a mixed opioid agonist, reduces cocaine self-administration through nociceptin opioid and mu opioid receptors. Front Psych 8:234Google Scholar
  68. Spagnolo B, Calo G, Polgar WE et al (2008) Activities of mixed NOP and mu-opioid receptor ligands. Br J Pharmacol 153:609–619PubMedGoogle Scholar
  69. Sukhtankar DD, Lagorio CH, Ko MC (2014) Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats. Eur J Pharmacol 745:182–189PubMedPubMedCentralGoogle Scholar
  70. Tian JH, Xu W, Fang Y et al (1997) Bidirectional modulatory effect of orphanin FQ on morphine-induced analgesia: antagonism in brain and potentiation in spinal cord of the rat. Br J Pharmacol 120:676–680PubMedGoogle Scholar
  71. Toll L (2013) The use of bifunctional NOP/mu and NOP receptor selective compounds for the treatment of pain, drug abuse, and psychiatric disorders. Curr Pharm Des 19:7451–7460Google Scholar
  72. Toll L, Khroyan TV, Polgar WE et al (2009) Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociception receptor/mu-opioid receptor ligands: implications for therapeutic applications. J Pharmacol Exp Ther 331:954–964PubMedPubMedCentralGoogle Scholar
  73. Toll L, Bruchas MR, Calo’ G et al (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68:419–457PubMedPubMedCentralGoogle Scholar
  74. Tzschentke TM, Rutten K (2018) Mu-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptor activation both contribute to the discriminative stimulus properties of cebranopadol in the rat. Neuropharmacology 129:100–108PubMedGoogle Scholar
  75. Tzschentke TM, De Vry J, Terlinden R et al (2006) Tapentadol HCl: analgesic, μ opioid receptor (MOR) agonist, noradrenaline reuptake inhibitor. Drugs Future 31:1053–1061Google Scholar
  76. Tzschentke TM, Christoph T, Kögel B et al (2007) (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 323:265–276PubMedGoogle Scholar
  77. Tzschentke TM, Jahnel U, Kögel B et al (2009) Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule. Drugs Today 45:483–496PubMedGoogle Scholar
  78. Tzschentke TM, Kögel BY, Frosch S et al (2017a) Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol.  https://doi.org/10.1111/adb.12550 PubMedGoogle Scholar
  79. Tzschentke TM, Linz K, Frosch S et al (2017b) Antihyperalgesic, antiallodynic, and antinociceptive effects of cebranopadol, a novel potent nociceptin/orphanin FQ and opioid receptor agonist, after peripheral and central administration in rodent models of neuropathic pain. Pain Pract 17:1032–1041PubMedGoogle Scholar
  80. Ueda H, Yamaguchi T, Tokuyama S et al (1997) Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci Lett 237:136–138Google Scholar
  81. Ueda H, Inoue M, Takeshima H et al (2000) Enhanced spinal nociceptin receptor expression develops morphine tolerance and dependence. J Neurosci 20:7640–7647PubMedPubMedCentralGoogle Scholar
  82. Walentiny DM, Wiebelhaus JM, Beardsley PM (2018) Nociceptin/orphanin FQ receptors modulate the discriminative stimulus effects of oxycodone in C57BL/6 mice. Drug Alcohol Depend 187:335–342PubMedGoogle Scholar
  83. Winger G, Hursh SR, Casey KL et al (2002) Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action. J Pharmacol Exp Ther 301:690–697PubMedGoogle Scholar
  84. Winter L, Nadeson R, Tucker AP et al (2003) Antinociceptive properties of neurosteroids: a comparison of alphadolone and alphaxalone in potentiation of opioid antinociception. Anesth Analg 97:798–805PubMedGoogle Scholar
  85. Yassen A, Olofsen E, Romberg R et al (2007) Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther 81:50–58PubMedGoogle Scholar
  86. Zaveri NT (2011) The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr Top Med Chem 11:1151–1156PubMedPubMedCentralGoogle Scholar
  87. Zaveri NT, Jiang F, Olsen C et al (2013) Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP receptor-selective scaffolds. Part I. Bioorg Med Chem Lett 23:3308–3313PubMedPubMedCentralGoogle Scholar
  88. Zaveri NT, Journigan VB, Polgar WE (2015) Discovery of the first small-molecule opioid pan antagonist with nanomolar affinity at mu, delta, kappa, and nociception opioid receptors. ACS Chem Neurosci 6:646–657PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Thomas M. Tzschentke
    • 1
    Email author
  • Klaus Linz
    • 1
  • Thomas Koch
    • 1
  • Thomas Christoph
    • 1
  1. 1.Grünenthal GmbH, Global InnovationAachenGermany

Personalised recommendations