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Cebranopadol Sale

(Synonyms: GRT6005) 目录号 : GC35637

A nociceptin-, µ-, ĸ-, and δ-opioid receptor agonist

Cebranopadol Chemical Structure

Cas No.:863513-91-1

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10mM (in 1mL DMSO)
¥1,107.00
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2mg
¥770.00
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5mg
¥1,330.00
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10mg
¥2,187.00
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50mg
¥5,898.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Kinase experiment:

Human MOP, DOP, KOP, and NOP receptor binding assays are run in microtiter plates with wheat germ agglutinin-coated scintillation proximity assay beads. [N-allyl-2,3-3H]naloxone and [tyrosyl-3,5-3H]deltorphin II, [3H]Ci-977, and [leucyl-3H]nociceptin are used as ligands for the MOP, DOP, KOP, and NOP receptor binding studies, respectively. The KD values of the radioligands used for the calculation of Ki values are provided as supplemental information. The assay buffer used for the MOP, DOP, and KOP receptor binding studies is 50 mM Tris-HCl (pH 7.4) supplemented with 0.052 mg/mL bovine serum albumin. For the NOP receptor binding studies, the assay buffer used is 50 mM HEPES, 10 mM MgCl2, 1 mM EDTA (pH 7.4). The final assay volume of 250 μL/well included 1 nM [3H]naloxone, 1 nM [3H]deltorphin II, 1 nM [3H]Ci-977, or 0.5 nM [3H]nociceptin as a ligand and cebranopadol in dilution series. Cebranopadol is diluted with 25% DMSO in water to yield a final 0.5% DMSO concentration, which also served as a respective vehicle control. Assays are started by the addition of beads (1 mg beads/well), which had been preloaded for 15 minutes at room temperature with 23.4 μg of human MOP membranes, 12.5 μg of human DOP membrane, 45 μg of human KOP membranes, or 25.4 µg of human NOP membranes per 250 µL of final assay volume. After short mixing, the assays are run for 90 minutes at room temperature. The microtiter plates are then centrifuged for 20 minutes at 500 rpm, and the signal rate is measured by means of a 1450 MicroBeta Trilux. IC50 values reflecting 50% displacement of [3H]naloxone-, [3H]deltorphin II-, [3H]Ci-977-, or [3H]nociceptin-specific receptor binding are calculated by nonlinear regression analysis. Individual experiments are run in duplicate and are repeated three times in independent experiments[1].

Animal experiment:

Rats[1] The pharmacokinetic properties of cebranopadol in rats are investigated after a single intravenous dose of 160 μg/kg cebranopadol. The intravenous dose is administered as a bolus in a volume of 2 mL/kg with a catheter in the vena femoralis. Blood samples (200 μL/sample) are withdrawn via an implanted arterial catheter (arteria carotis) by an automated blood sampling system at the following sampling times: 0 (predose), 5, 15, 30, 60, 180, 360, 720, and 1440 minutes after administration. Blood samples are centrifuged, and plasma is separated. Plasma concentrations of cebranopadol are determined using a validated liquid chromatography-tandem mass spectrometry method. The lower limit of quantification for cebranopadol in this method is 0.05 ng/mL using a sample volume of 50 µL of plasma.

References:

[1]. Linz K, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014 Jun;349(3):535-48.
[2]. de Guglielmo G, et al. 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.
[3]. Satat K, et al. 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. 2017 Oct 25.

产品描述

Cebranopadol is an agonist of nociceptin-, µ-, ĸ-, and δ-opioid receptor agonist (Kis = 0.9, 0.7, 2.6, and 18 nM, respectively).1 It is greater than 100-fold selective for these receptors over a panel of more than 100 ion channels, neurotransmitter transporters, receptors, and enzymes, but does bind to the serotonin (5-HT) receptor subtype 5-HT5A with a Ki value of 8.7 nM. Cebranopadol inhibits nociceptin-, DAMGO-, and SNC 80-induced GTPɣS binding in CHO cells expressing nociceptin-, µ-, and δ-opioid receptors, respectively (EC50s = 13, 1.2, and 110 nM, respectively), as well as U69,593-induced GTPɣS binding in HEK293 cells expressing the ĸ-opioid receptor (EC50 = 17 nM). It increases the paw withdrawal threshold in rat models of bone cancer pain and streptozotocin-induced diabetic neuropathy (ED50s = 3.6 and 0.5 µg/kg, respectively, i.v.). Cebranopadol also increases paw weight bearing on the ipsilateral side in a rat model of arthritis induced by complete Freund's adjuvant (CFA) and M. tuberculosis (ED50 = 5.5 µg/kg, i.v.).

1.Linz, K., Christoph, T., Tzschentke, T.M., et al.Cebranopadol: A novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonistJ. Pharmacol. Exp. Ther.349(3)535-548(2014)

Chemical Properties

Cas No. 863513-91-1 SDF
别名 GRT6005
Canonical SMILES CN(C)[C@]1(C2=CC=CC=C2)CC[C@]3(C(N4)=C(CCO3)C5=C4C=CC(F)=C5)CC1
分子式 C24H27FN2O 分子量 378.48
溶解度 DMSO: 6.67 mg/mL (17.62 mM); Water: < 0.1 mg/mL (insoluble) 储存条件 Store at -20°C
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1 mM 2.6421 mL 13.2107 mL 26.4215 mL
5 mM 0.5284 mL 2.6421 mL 5.2843 mL
10 mM 0.2642 mL 1.3211 mL 2.6421 mL
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Research Update

Cebranopadol as a Novel Promising Agent for the Treatment of Pain

Molecules 2022 Jun 21;27(13):3987.PMID:35807228DOI:10.3390/molecules27133987.

Opioids are used to treat pain, but despite their effectiveness, they possess several side effects such as respiratory depression, tolerance and physical dependence. Cebranopadol has been evaluated as a solution to this problem. The compound acts on the mu opioid receptor and the nociceptin/orphanin receptor and these receptors co-activation can reduce opioid side-effects without compromising analgesia. In the present review, we have compiled information on the effects of Cebranopadol, its pharmacokinetics, and clinical trials involving Cebranopadol, to further explore its promise in pain management.

Cebranopadol: novel dual opioid/NOP receptor agonist analgesic

J Clin Pharm Ther 2017 Feb;42(1):8-17.PMID:27778406DOI:10.1111/jcpt.12461.

What is known and objective: Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide (NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of Cebranopadol. Methods: Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for Cebranopadol in particular. The identified sources were reviewed and the information synthesized. Results: The preclinical testing of Cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. What is new and conclusion: Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials.

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.PMID:25865744DOI:10.1517/13543784.2015.1036985.

Introduction: Pain is a syndrome of various clinical disorders, which arises from various pathological conditions and which presents significant challenges in both its diagnosis and treatment. There is currently a strong medical demand to develop new therapies with a higher efficacy and a better tolerability profile. Areas covered: In this review, the authors report on the available data for the pharmacological properties of Cebranopadol (GRT6005), a first in-class, potent analgesic compound which acts as an agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors. They highlight the in vitro receptor binding studies, as well as the in vivo preclinical results on the analgesic efficacy of Cebranopadol obtained in several rodent pain models. The authors also briefly summarize the available data from clinical trials with Cebranopadol. Expert opinion: 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. Hence, it seems to possess a broader therapeutic window than classical opioids. While it is particularly interesting as a novel, potent bifunctional agonist of NOP/opioid receptors, the outcome of its ongoing and planned clinical trials will be crucial for its future development and potential application in humans.

Functional Profile of Systemic and Intrathecal Cebranopadol in Nonhuman Primates

Anesthesiology 2021 Sep 1;135(3):482-493.PMID:34237134DOI:10.1097/ALN.0000000000003848.

Background: Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether Cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods: The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of Cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results: Subcutaneous Cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose-response curve of Cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., Cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic Cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal Cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions: In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, Cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although Cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of Cebranopadol.

Cebranopadol reduces cocaine self-administration in male rats: Dose, treatment and safety consideration

Neuropharmacology 2020 Aug 1;172:108128.PMID:32389751DOI:10.1016/j.neuropharm.2020.108128.

As a novel first-in-class potent analgesic acting as an agonist of multiple opioid receptors, Cebranopadol showed high efficacy and good tolerability in a broad range of preclinical models and clinical trials related to pain. In the present study, to evaluate the efficacy and safety of Cebranopadol as a potential treatment of cocaine dependence, we tested the effects of Cebranopadol with single and repeated doses (25, 50, 75, or 100 μg/kg, oral gavage) using rat models of cocaine fixed-ratio (FR) self-administration (SA), cocaine progressive-ratio (PR) SA, and sucrose pellet SA. In single-dosing treatment paradigm, Cebranopadol significantly and dose-dependently reduced cocaine SA under FR and PR schedules and suppressed food intake under FR schedule without causing apparent side effects. In repeated-dosing treatment scheme, i.e. daily administration of 25, 50, 75, or 100 μg/kg Cebranopadol for a week, the similar reduction in cocaine intake was detected, while non-negligible complications/side effects were observed at repeated high doses (75 and 100 μg/kg). The observed side effects were similar to the common toxic signs elicited by heroin at high doses, although Cebranopadol did not fully substitute heroin's discriminative stimulant effects in our drug discriminative tests. These results demonstrated that the most appropriate oral dose of Cebranopadol to balance the efficacy and safety is 50 μg/kg. Collectively, although Cebranopadol may serve as a new treatment for cocaine dependence, more consideration, cautiousness, and a clear optimal dose window to dissociate its therapeutic effects from opioid side effects/complications in male and female subjects will be necessary to increase its practical clinical utility.