CebranopadolORL-1 agonist CAS# 863513-91-1 |
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| Cas No. | 863513-91-1 | SDF | Download SDF |
| PubChem ID | 11848225 | Appearance | Powder |
| Formula | C24H27FN2O | M.Wt | 378.48 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | GRT-6005;GRT 6005;GRT6005 | ||
| Solubility | DMSO : 6.67 mg/mL (17.62 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
| Chemical Name | 6-fluoro-N,N-dimethyl-1'-phenylspiro[4,9-dihydro-3H-pyrano[3,4-b]indole-1,4'-cyclohexane]-1'-amine | ||
| SMILES | CN(C)C1(CCC2(CC1)C3=C(CCO2)C4=C(N3)C=CC(=C4)F)C5=CC=CC=C5 | ||
| Standard InChIKey | CSMVOZKEWSOFER-UHFFFAOYSA-N | ||
| Standard 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 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | 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:Cebranopadol binds with high affinity (subnanomolar to nanomolar range) to nociceptin/orphanin FQ peptide (NOP) and opioid receptors, with Ki of 1±0.5 nM, 2.4±1.2 nM, and 64±11 nM for rat NOP, mu-opioid peptide (MOP) receptor, and kappa-opioid peptide (KOP) receptor, and with Ki of 0.9±0.2 nM, 0.7±0.3 nM, and 2.6±1.4 nM for Rat NOP, MOP, and KOP receptor[1].In Vivo: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[1]. References: | |||||
Cebranopadol Dilution Calculator
Cebranopadol Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6421 mL | 13.2107 mL | 26.4215 mL | 52.843 mL | 66.0537 mL |
| 5 mM | 0.5284 mL | 2.6421 mL | 5.2843 mL | 10.5686 mL | 13.2107 mL |
| 10 mM | 0.2642 mL | 1.3211 mL | 2.6421 mL | 5.2843 mL | 6.6054 mL |
| 50 mM | 0.0528 mL | 0.2642 mL | 0.5284 mL | 1.0569 mL | 1.3211 mL |
| 100 mM | 0.0264 mL | 0.1321 mL | 0.2642 mL | 0.5284 mL | 0.6605 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Cebranopadol is a potent nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [1][2][3][4].
Nociceptin/orphanin FQ peptide (NOP) and opioid are available analgesics. They provide sufficient efficacy in many pain syndromes. However, they are not effective enough in neuropathic pain [1].
Cebranopadol showed the highest receptor affinities at NOP and MOP of rat and human, while the affinity at KOP receptors was 3-38 fold lower affinity for KOP in the human and rat. Compare with NOP or MOP, affinity for DOP in humans is 20-fold lower [1][2].
In model rats, Cebranopadol was antinociceptive after intravenous and oral administration.
And its activity lasted longer (7 h) than that of same doses of fentanyl (30 min) and morphine (3 h). Also, intravenous cebranopadol was also useful in chronic pain models: the spinal nerve ligation model, bone cancer pain, painful diabetic neuropathy and complete Freund’s adjuvant (CFA)-induced arthritis [1].
References:
[1]. 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 , 12: 1-8.
[2]. Lambert DG, Bird MF, Rowbotham DJ, et al. Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist. Br J Anaesth, 2015, 114(3): 364-366.
[3]. Schunk S, Linz K, Hinze C, et al. Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol. ACS Med Chem Lett, 2014, 5(8): 857-862.
[4]. Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther, 2014, 349(3): 535-548.
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Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist.[Pubmed:28116100]
Pharmacol Res Perspect. 2016 Aug 2;4(4):e00247.
The aim of the study was to investigate the in vitro and in vivo pharmacological profile of Cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro Cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G-proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G-protein and beta-arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating Cebranopadol antinociceptive properties. In calcium mobilization studies Cebranopadol showed the following rank order of potency NOP = mu > kappa >/= delta. In BRET studies, Cebranopadol promoted NOP and mu receptors interaction with G-protein with similar high potency and efficacy. However, Cebranopadol did not stimulated NOP-beta-arrestin 2 interactions and displayed reduced potency at mu/beta-arrestin 2. In vivo, Cebranopadol exhibits highly potent and extremely long-lasting antinociceptive effects. The effects of Cebranopadol in the tail withdrawal assay were sensitive to both SB-612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that Cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.
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.[Pubmed:28112482]
Pain Pract. 2017 Nov;17(8):1032-1041.
Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where Cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. In STZ-treated rats, Cebranopadol (i.pl.) reduced mechanical hypersensitivity in the ipsilateral paw, but had no effect at the contralateral paw. In CCI rats, Cebranopadol (i.pl.) showed antiallodynic activity at the ipsilateral paw. After administration to the contralateral paw, Cebranopadol also showed ipsilateral antiallodynic activity, but with reduced potency and delayed onset. In diabetic mice, Cebranopadol i.th. and i.c.v. decreased heat hyperalgesia with full efficacy and similar potency for both routes. Cebranopadol also produced significant antinociception in nondiabetic controls. Thus, Cebranopadol exerts potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects after local/peripheral, spinal, and supraspinal administration. The contralateral effects after i.pl. administration were likely due to systemic redistribution. After central administration of Cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that Cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.
Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers.[Pubmed:28291085]
Anesthesiology. 2017 Apr;126(4):697-707.
BACKGROUND: Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify Cebranopadol's respiratory effects. METHODS: Twelve healthy male volunteers received 600 mug oral Cebranopadol as a single dose. The following main endpoints were obtained at regular time intervals for 10 to 11 h after drug intake: ventilation at an elevated clamped end-tidal pressure of carbon dioxide, pain threshold and tolerance to a transcutaneous electrical stimulus train, and plasma Cebranopadol concentrations. The data were analyzed using sigmoid Emax (respiration) and power (antinociception) models. RESULTS: Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The blood-effect-site equilibration half-life for respiratory depression and analgesia was 1.2 +/- 0.4 h (median +/- standard error of the estimate) and 8.1 +/- 2.5 h, respectively. The effect-site concentration causing 50% respiratory depression was 62 +/- 4 pg/ml; the effect-site concentration causing 25% increase in currents to obtain pain threshold and tolerance was 97 +/- 29 pg/ml. The model estimate for minimum ventilation was greater than zero at 4.9 +/- 0.7 l/min (95% CI, 3.5 to 6.6 l/min). CONCLUSIONS: At the dose tested, Cebranopadol produced respiratory depression with an estimate for minimum ventilation greater than 0 l/min. This is a major advantage over full mu-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.
Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin/Orphanin FQ Peptide Receptor Agonist Activity.[Pubmed:28291086]
Anesthesiology. 2017 Apr;126(4):708-715.
BACKGROUND: Cebranopadol is a first-in-class analgesic with agonist activity at classic opioid peptide receptors and the nociceptin/orphanin FQ peptide receptor. The authors compared the antinociceptive and respiratory depressant effects of Cebranopadol and the classic opioid fentanyl and used selective antagonists to provide the first mechanistic evidence of the contributions of the nociceptin/orphanin FQ peptide and mu-opioid peptide receptors to Cebranopadol's respiratory side-effect profile. METHODS: Antinociception was assessed in male Sprague-Dawley rats using the low-intensity tail-flick model (n = 10 per group). Arterial blood gas tensions (PaCO2 and PaO2) were measured over time in samples from unrestrained, conscious rats after intravenous administration of Cebranopadol or fentanyl (n = 6 per group). RESULTS: The ED50 for peak antinociceptive effect in the tail-flick model was 7.4 mug/kg for Cebranopadol (95% CI, 6.6 to 8.2 mug/kg) and 10.7 mug/kg for fentanyl citrate (9 to 12.7 mug/kg). Fentanyl citrate increased PaCO2 levels to 45 mmHg (upper limit of normal range) at 17.6 mug/kg (95% CI, 7.6 to 40.8 mug/kg) and to greater than 50 mmHg at doses producing maximal antinociception. In contrast, with Cebranopadol, PaCO2 levels remained less than 35 mmHg up to doses producing maximal antinociception. The nociceptin/orphanin FQ peptide receptor antagonist J-113397 potentiated the respiratory depressant effects of Cebranopadol; these changes in PaCO2 and PaO2 were fully reversible with the mu-opioid peptide receptor antagonist naloxone. CONCLUSIONS: The therapeutic window between antinociception and respiratory depression in rats is larger for Cebranopadol than that for fentanyl because the nociceptin/orphanin FQ peptide receptor agonist action of Cebranopadol counteracts side effects resulting from its mu-opioid peptide receptor agonist action.
