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Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics.

Background: Neuropathic pain is drug-resistant to available analgesics and therefore novel treatment options for this debilitating clinical condition are urgently needed. Recently, two drug candidates, namely mirogabalin and cebranopadol have become a subject of interest because of their potential utility as analgesics for chronic pain treatment. However, they have not been investigated thoroughly in some types of neuropathic pain, both in humans and experimental animals. Methods: This study used the von Frey test, the hot plate test and the two-plate thermal place preference test supported by image analysis and machine learning to assess the effect of intraperitoneal mirogabalin and subcutaneous cebranopadol on mechanical and thermal nociceptive threshold in mouse models of neuropathic pain induced by streptozotocin, paclitaxel and oxaliplatin. Results: Mirogabalin and cebranopadol effectively attenuated tactile allodynia in models of neuropathic pain induced by streptozotocin and paclitaxel. Cebranopadol was more effective than mirogabalin in this respect. Both drugs also elevated the heat nociceptive threshold in mice. In the oxaliplatin model, cebranopadol and mirogabalin reduced cold-exacerbated pain. Conclusions: Since mirogabalin and cebranopadol are effective in animal models of neuropathic pain, they seem to be promising novel therapies for various types of neuropathic pain in patients, in particular those who are resistant to available analgesics. [ABSTRACT FROM AUTHOR]

Cocaine use disorder is a psychiatric condition affecting millions of people worldwide. Up till now, there are no FDA approved medications reported against this disorder. Previous pharmacological studies suggested that, simultaneously targeting all types of opioid receptors, some agonistically while others antagonistically have been proven a much useful strategy for the treatment of cocaine addiction. Recent evidence indicated that a novel agonist cebranopadol has a high binding affinity towards Nociceptin opioid receptor (NOP) and Mu opioid receptor (MOP), and partial affinity with Kappa opioid receptor (KOP) and Delta opioid receptor (DOP). Interestingly, in vivo studies revealed that cebranopadol blocked the cocaine seeking in animal models. In the present study, quantum chemical calculations were performed to calculate various thermodynamic parameters of cebranopadol using density functional theory. Flexible docking was performed to rationalize the molecular basis of cis and trans isomers of cebranopadol. Further, the atomistic description of activation mechanism of MOP receptor by cebranopadol investigated by sub‐microsecond timescale molecular dynamic (MD) simulation. Our results revealed that the operating mode of the activation switch composed of Trp2936.48 and Asn3287.45 residues, was accountable for down‐ and up‐regulation, respectively, of the β‐arrestin signaling. This particular conformational change in turn affected the G‐protein‐biased activation of MOP receptor. Cebranopadol stabilized the Asn3287.45 by mediating halogen bond formation. According to best of our knowledge, this is the first mechanistic study of cebranopadol with MOP receptor using the quantum mechanical calculations and MD simulations to explain the inhibition of cocaine addiction. [ABSTRACT FROM AUTHOR]

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 is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 μg/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 hour) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.

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. [ABSTRACT FROM AUTHOR]

Cebranopadol is a novel, centrally acting, potent, first‐in‐class analgesic drug candidate with a unique mode of action that combines nociceptin/orphanin FQ peptide receptor and opioid peptide receptor agonism. The present study aimed to develop and validate a novel UHPLC‐MS/MS method to quantify cebranopadol in rabbit plasma and to assess its pharmacokinetics in rabbits after subcutaneous (s.c.) administration. Twelve adult females were administered with 200 µg/kg s.c. injection. Blood samples were withdrawn at 15, 30 and 45 min and 1, 1.5, 2, 4, 6, 8, 10 and 24 hr after administration. The plasma samples were extracted with a liquid/liquid extraction. The new analytical method complied with the EMA requirements for the bioanalytical method validation. The method was selective, repeatable, accurate, precise and robust with a lower limit of quantification of 0.1 ng/ml. In all the rabbits, cebranopadol was quantifiable from 0.25 to 10 hr. Mean Cmax and Tmax were 871 ng/ml and 0.25 hr, respectively. Further studies including the i.v. administration are necessary to fully evaluate the pharmacokinetic features of this novel active compound. [ABSTRACT FROM AUTHOR]

Abstract A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexane-dihydropyrano[3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain.