Cebranopadol
[CAS# 863513-91-1]

Identification

• Classification: API >> Antibiotics
• Name: Cebranopadol
• Synonyms: (1alpha,4beta)-6'-Fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine; GRT 6005
• Molecular Formula: C₂₄H₂₇FN₂O
• Molecular Weight: 378.48
• CAS Registry Number: 863513-91-1
• SMILES: CN(C)C1(CCC2(CC1)C3=C(CCO2)C4=C(N3)C=CC(=C4)F)C5=CC=CC=C5

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 547.5±50.0 ºC 760 mmHg (Calc.)^*
• Flash point: 284.9±30.1 ºC (Calc.)^*
• Solubility: 10 mM (DMSO), 100 mM (ethanol) (Expl.)
• Index of refraction: 1.644 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GH07 Warning
• Hazard Statements: H302-H315-H319-H335
• Precautionary Statements: P261-P305+P351+P338

Discovory and Applicatios

Cebranopadol is a potent analgesic compound developed to combine actions on classical opioid receptors and the nociceptin/orphanin FQ peptide (NOP) receptor, aiming to provide strong pain relief with fewer side effects than conventional opioids. The concept of co-activation of the mu opioid (MOP) receptor and the NOP receptor underlies its design, to achieve synergistic analgesia while moderating typical opioid liabilities.

The discovery of cebranopadol was first described in an ACS Medicinal Chemistry Letters article in 2014, which reported its design as a “first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors.” In that work, the authors characterized its binding affinities and functional agonism at multiple receptor subtypes, demonstrating its mixed profile. Subsequent pharmacological and preclinical studies confirmed that cebranopadol functions as a full agonist at MOP and delta opioid receptors, and as a partial agonist at the NOP and kappa opioid receptors, placing it in a unique pharmacological niche. Its central penetration and oral bioavailability made it a promising candidate for chronic pain therapy.

Preclinical evaluation of cebranopadol showed prolonged analgesic effects in animal models. In rodents, a single administration produced antinociception lasting several hours, exceeding the duration of classic opioids in equivalent doses. It showed efficacy across various pain modalities, including acute nociceptive pain, inflammatory pain, neuropathic pain, and cancer-related pain. In many models, cebranopadol showed stronger effects in neuropathic pain than in acute nociceptive settings, which is notable since neuropathic pain is often refractory to standard opioids. Importantly, in animal trials, cebranopadol exhibited reduced respiratory depression and dependency risks compared to equi-analgesic doses of morphine, possibly linked to its NOP receptor activity that counterbalances some adverse effects of MOP activation.

Pharmacokinetic and safety studies in animals and early human trials showed that cebranopadol is rapidly absorbed, extensively distributed, and has a long half-life appropriate for once-daily dosing. Oral formulations achieved steady levels compatible with sustained analgesia. Safety testing, especially in rodents, suggested a tolerable side effect profile: in balance and motor coordination assays, cebranopadol did not show significant impairment at effective analgesic doses. Respiratory parameters were less depressed than with classical opioids in comparable analgesic conditions, supporting its therapeutic promise.

Clinically, cebranopadol has progressed into human trials. In a phase II randomized, double-blind study in patients with chronic low back pain, doses of cebranopadol (200, 400, or 600 µg once daily) demonstrated statistically significant pain reduction compared to placebo and comparable efficacy to tapentadol as an active control. Tolerability was acceptable in those who reached target doses, though higher doses had somewhat increased treatment discontinuations during titration. The compound also showed favorable effects on sleep and functional outcomes in those trials. Furthermore, early clinical experience suggests that cebranopadol may deliver analgesia with reduced incidence of classic opioid side effects, although detailed long-term safety and abuse liability assessments remain ongoing.

The application of cebranopadol is primarily in pain management, with emphasis on chronic, neuropathic, inflammatory, and cancer pain syndromes. Its design as a dual NOP/opioid agonist is intended to make it suitable for long-term use with fewer side effects such as tolerance, dependence, and respiratory depression. In addition, its use is being explored in experimental models of addiction: in studies involving cocaine self-administration in rodents, cebranopadol reduced cocaine intake, implicating its influence on reward pathways through both NOP and opioid receptor action.

Because of its novel mechanism, cebranopadol represents a new class of analgesic agents, bridging traditional opioid pharmacology and NOP modulation. While it has shown promising efficacy and safety in early trials, its ultimate clinical role will depend on larger, long-term studies assessing sustained analgesic benefit, safety, abuse potential, and comparative advantage over existing analgesics.

References

Schunk S, Hoffmann C, Huber W, et al (2014) Discovery of a potent analgesic NOP and opioid receptor agonist: cebranopadol. ACS Medicinal Chemistry Letters 5(8). DOI: 10.1021/ml500117c

Linz K, Brackemeyer J, Matthes HWD, et al (2014) Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. Journal of Clinical Pharmacy and Therapeutics 42(1). DOI: 10.1111/jcpt.12461

Fantinati A, La Regina G, Casalesi M, et al (2017)