Cebranopadol | GRT-6005 | CAS#863513-91-1 | 863513-92-2 | Opioid Receptor Agonist

MedKoo Cat#: 319710 | Name: Cebranopadol

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Cebranopadol, also known as GRT-6005, is a Opioid Receptor Agonist with agonistic activity at nociceptin/orphanin FQ and opioid receptors. Cebranopadol displays analgesic, antiallodynic and antihyperalgesic properties in several rat models of acute nociceptive, inflammatory, cancer and neuropathic pain. In contrast to classical opioids, it has a higher analgesic potency in models of neuropathic pain than in acute nociceptive pain. Even at higher analgesic doses, cebranopadol does not induce motor coordination deficits or respiratory depression in rats.

Chemical Structure

Cebranopadol

CAS#863513-91-1 (free base)

Theoretical Analysis

MedKoo Cat#: 319710

Name: Cebranopadol

CAS#: 863513-91-1 (free base)

Chemical Formula: C24H27FN2O

Exact Mass: 378.2107

Molecular Weight: 378.49

Elemental Analysis: C, 76.16; H, 7.19; F, 5.02; N, 7.40; O, 4.23

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 950.00	Ready to ship
500mg	USD 1,950.00	Ready to ship
1g	USD 3,250.00	2 weeks
2g	USD 5,450.00	2 Weeks

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Related CAS #

863513-92-2 (hemicitrate) 863513-91-1 (free base)

Synonym

GRT-6005; GRT 6005; GRT6005; Cebranopadol

IUPAC/Chemical 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

InChi Key

CSMVOZKEWSOFER-RQNOJGIXSA-N

InChi Code

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-

SMILES Code

CN(C)[C@]1(C2=CC=CC=C2)CC[C@]3(C(N4)=C(CCO3)C5=C4C=CC(F)=C5)CC1

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Related CAS# 863513-92-2 (Cebranopadol Hemicitrate) 863513-91-1 (Cebranopadol)

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T9D07P01

QC Data

View QC data: current batch, Lot#T9D07P01

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Cebranopadol is an analgesic NOP and opioid receptor agonist with Kis/EC50s of 0.9 nM/13 nM, 0.7 nM/1.2 nM, 2.6 nM/17 nM, 18 nM/110 nM for human NOP, MOP, KOP and delta-opioid peptide (DOP) receptor, respectively.

In vitro activity:

Cebranopadol displays high (sub)nanomolar (nm) affinity for NOP and opioid receptors (Fig. 2) in human receptor binding assays (Table 1).68, 69 The intrinsic activity (in vitro efficacy) of cebranopadol was assessed using [35S]GTPγS binding assays with human (h) NOP and opioid receptors expressed in transfected cell lines. GTPγS is a non-hydrolysable or only slowly hydrolysable G-protein-activating analogue of GTP; activity in this assay indicates the degree of agonist activity. Cebranopadol was compared to a selected ‘full agonist’ (100% intrinsic activity) at each of the receptor (sub)types: nociceptin/orphanin FQ for the hNOP receptor; the peptide DAMGO ([D-Ala2,N-MePhe4,Gly-ol]-enkephalin) for the hMOP receptor; SNC 80 (4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide) for hDOR; and U69,593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4·5]dec-8-yl]acetamide) for hKOR. Cebranopadol was found to be a full agonist (100%) at DOR and MOR, nearly a full agonist (~90%) at NOP receptors and a partial agonist (~70%) at KOR (Table 1).68 Binding assays for more than 100 receptors, ion channels and enzymes showed that off-target receptor affinity was 100- to 1000-fold lower than target (opioid and NOP receptor) affinity. Activity at the serotonin 5A (5-HT5A) receptor was revealed (Ki = 8·7 nm), but a [35S]GTPγS binding assay for functional activity at human 5-HT5A revealed no significant functional activity (agonistic or antagonistic) at concentrations up to 10 μm. Reference: J Clin Pharm Ther. 2017 Feb;42(1):8-17. https://doi.org/10.1111/jcpt.12461

In vivo activity:

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 is 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 is partially reversed by pretreatment with the selective NOP receptor antagonist J-113397 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 is 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. Reference: J Pharmacol Exp Ther. 2014 Jun;349(3):535-48. https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=24713140

	Solvent	mg/mL	mM
Solubility
	DMSO	6.7	17.62

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 378.49 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Raffa RB, Burdge G, Gambrah J, Kinecki HE, Lin F, Lu B, Nguyen JT, Phan V, Ruan A, Sesay MA, Watkins TN. Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. J Clin Pharm Ther. 2017 Feb;42(1):8-17. doi: 10.1111/jcpt.12461. Epub 2016 Oct 24. PMID: 27778406. 2. Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schröder W, Kögel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014 Jun;349(3):535-48. doi: 10.1124/jpet.114.213694. Epub 2014 Apr 8. PMID: 24713140.

In vivo protocol:

1: Ziemichod W, Kotlinska J, Gibula-Tarlowska E, Karkoszka N, Kedzierska E. Cebranopadol as a Novel Promising Agent for the Treatment of Pain. Molecules. 2022 Jun 21;27(13):3987. doi: 10.3390/molecules27133987. PMID: 35807228; PMCID: PMC9268744. 2: Raffa RB, Burdge G, Gambrah J, Kinecki HE, Lin F, Lu B, Nguyen JT, Phan V, Ruan A, Sesay MA, Watkins TN. Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. J Clin Pharm Ther. 2017 Feb;42(1):8-17. doi: 10.1111/jcpt.12461. Epub 2016 Oct 24. PMID: 27778406. 3: Sałat K, Jakubowska A, Kulig K. Cebranopadol : a first-in-class potent analgesic agent with agonistic activity at nociceptin/orphanin FQ and opioid receptors. Expert Opin Investig Drugs. 2015 Jun;24(6):837-44. doi: 10.1517/13543784.2015.1036985. Epub 2015 Apr 12. PMID: 25865744. 4: Ding H, Trapella C, Kiguchi N, Hsu FC, Caló G, Ko MC. Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates. Anesthesiology. 2021 Sep 1;135(3):482-493. doi: 10.1097/ALN.0000000000003848. PMID: 34237134; PMCID: PMC8446297. 5: Wei H, Zhang T, Zhan CG, Zheng F. Cebranopadol reduces cocaine self- administration in male rats: Dose, treatment and safety consideration. Neuropharmacology. 2020 Aug 1;172:108128. doi: 10.1016/j.neuropharm.2020.108128. Epub 2020 May 8. PMID: 32389751; PMCID: PMC9334146. 6: Wei H, Shang L, Zhan CG, Zheng F. Effects of Cebranopadol on Cocaine-induced Hyperactivity and Cocaine Pharmacokinetics in Rats. Sci Rep. 2020 Jun 9;10(1):9254. doi: 10.1038/s41598-020-66250-z. PMID: 32518276; PMCID: PMC7283222. 7: Łebkowska-Wieruszewska B, Gbylik-Sikorska M, Gajda A, Sartini I, Lisowski A, Poapolathep A, Giorgi M. Cebranopadol, a novel first-in-class drug candidate: Method validation and first exploratory pharmacokinetic study in rabbits. J Vet Pharmacol Ther. 2021 Jul;44(4):516-521. doi: 10.1111/jvp.12948. Epub 2021 Jan 25. PMID: 33491237. 8: de Guglielmo G, Matzeu A, Kononoff J, Mattioni J, Martin-Fardon R, George O. Cebranopadol Blocks the Escalation of Cocaine Intake and Conditioned Reinstatement of Cocaine Seeking in Rats. J Pharmacol Exp Ther. 2017 Sep;362(3):378-384. doi: 10.1124/jpet.117.241042. Epub 2017 Jun 23. PMID: 28645915; PMCID: PMC5539589. 9: Scholz A, Bothmer J, Kok M, Hoschen K, Daniels S. Cebranopadol: A Novel, First-in-Class, Strong Analgesic: Results from a Randomized Phase IIa Clinical Trial in Postoperative Acute Pain. Pain Physician. 2018 May;21(3):E193-E206. PMID: 29871387. 10: Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schröder W, Kögel BY, Beier H, Englberger W, Schunk S, De Vry J, Jahnel U, Frosch S. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014 Jun;349(3):535-48. doi: 10.1124/jpet.114.213694. Epub 2014 Apr 8. PMID: 24713140. 11: Shen Q, Deng Y, Ciccocioppo R, Cannella N. Cebranopadol, a Mixed Opioid Agonist, Reduces Cocaine Self-administration through Nociceptin Opioid and Mu Opioid Receptors. Front Psychiatry. 2017 Nov 13;8:234. doi: 10.3389/fpsyt.2017.00234. PMID: 29180970; PMCID: PMC5693905. 12: Kleideiter E, Piana C, Wang S, Nemeth R, Gautrois M. Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic. Clin Pharmacokinet. 2018 Jan;57(1):31-50. doi: 10.1007/s40262-017-0545-1. Erratum in: Clin Pharmacokinet. 2018 Aug;57(8):1057-1058. PMID: 28623508; PMCID: PMC5766727. 13: Nair AS, Mantha SP, Pulipaka SK, Rayani BK. Cebranopadol: A First-in-Class Nociceptin Receptor Agonist for Managing Chronic Pain. Indian J Palliat Care. 2020 Jan-Mar;26(1):147-148. doi: 10.4103/IJPC.IJPC_117_19. Epub 2020 Jan 28. PMID: 32132804; PMCID: PMC7017681. 14: Tzschentke TM, Linz K, Koch T, Christoph T. Cebranopadol: A Novel First-in- Class Potent Analgesic Acting via NOP and Opioid Receptors. Handb Exp Pharmacol. 2019;254:367-398. doi: 10.1007/164_2019_206. PMID: 30927089. 15: Lambert DG, Bird MF, Rowbotham DJ. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth. 2015 Mar;114(3):364-6. doi: 10.1093/bja/aeu332. Epub 2014 Sep 23. PMID: 25248647. 16: Koch ED, Kapanadze S, Eerdekens MH, Kralidis G, Létal J, Sabatschus I, Ahmedzai SH. Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks. J Pain Symptom Manage. 2019 Sep;58(3):390-399. doi: 10.1016/j.jpainsymman.2019.05.012. Epub 2019 May 30. PMID: 31152783. 17: Ruzza C, Holanda VA, Gavioli EC, Trapella C, Calo G. NOP agonist action of cebranopadol counteracts its liability to promote physical dependence. Peptides. 2019 Feb;112:101-105. doi: 10.1016/j.peptides.2018.12.001. Epub 2018 Dec 12. PMID: 30550769. 18: Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017 Sep;158(9):1813-1824. doi: 10.1097/j.pain.0000000000000986. PMID: 28644196; PMCID: PMC5761752. 19: Tzschentke TM, Kögel BY, Frosch S, Linz K. Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol. 2018 Sep;23(5):1010-1019. doi: 10.1111/adb.12550. Epub 2017 Sep 25. PMID: 28944554. 20: Dahan A, Olofsen E. Does Divergence Exist between Animal and Human Data on the Effect of Cebranopadol? Anesthesiology. 2021 Sep 1;135(3):382-383. doi: 10.1097/ALN.0000000000003885. PMID: 34329373.