Klaus Linz

Cebranopadol: a Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist

Cebranopadol (trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [Ki (nM)/EC50 (nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. 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 was 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 was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] 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 was 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.

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

We report the discovery of spiro[cyclohexane-pyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet-Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3-5, ethers 6 and 7, amines 8-10, 22-24, and 26-28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors.

Opioid-type Respiratory Depressant Side Effects of Cebranopadol in Rats Are Limited by Its Nociceptin/Orphanin FQ Peptide Receptor Agonist Activity

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 &mgr;-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 &mgr;g/kg for cebranopadol (95% CI, 6.6 to 8.2 &mgr;g/kg) and 10.7 &mgr;g/kg for fentanyl citrate (9 to 12.7 &mgr;g/kg). Fentanyl citrate increased PaCO2 levels to 45 mmHg (upper limit of normal range) at 17.6 &mgr;g/kg (95% CI, 7.6 to 40.8 &mgr;g/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 &mgr;-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 &mgr;-opioid peptide receptor agonist action.

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

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.

Limited potential of cebranopadol to produce opioid-type physical dependence in rodents

Cebranopadol is a novel potent analgesic agonist at the nociceptin/orphanin FQ peptide (NOP) and classical opioid receptors. As NOP receptor activation has been shown to reduce side effects related to the activation of μ‐opioid peptide (MOP) receptors, the present study evaluated opioid‐type physical dependence produced by cebranopadol in mice and rats. In a naloxone‐precipitated withdrawal assay in mice, a regimen of seven escalating doses of cebranopadol over 2 days produced only very limited physical dependence as evidenced by very little withdrawal symptoms (jumping) even at cebranopadol doses clearly exceeding the analgesic dose range. In contrast, mice showed clear withdrawal symptoms when treated with morphine within the analgesic dose range. In the rat, spontaneous withdrawal (by cessation of drug treatment; in terms of weight loss and behavioral score) was studied after 4‐week subacute administration. Naloxone‐precipitated withdrawal (in terms of weight loss and behavioral score) was studied in the same groups of rats after 1‐week re‐administration following the spontaneous withdrawal period. In both tests, cebranopadol‐treated rats showed only few signs of withdrawal, while withdrawal effects in rats treated with morphine were clearly evident. These findings demonstrate a low potential of cebranopadol to produce opioid‐type physical dependence in rodents. The prospect of this promising finding into the clinical setting remains to be established.

Nociceptin/orphanin FQ opioid peptide (NOP) receptor and µ-opioid peptide (MOP) receptors both contribute to the anti-hypersensitive effect of cebranopadol in a rat model of arthritic pain

ABSTRACT Cebranopadol is a novel, first‐in‐class analgesic with agonist activity at the nociceptin/orphanin FQ opioid peptide (NOP) receptor as well as the classical opioid peptide receptors. This study investigated the anti‐hypersensitive effect of cebranopadol in a rat model of arthritic pain. Selective antagonists were used to probe the involvement of the NOP receptor and the &mgr;‐opioid peptide (MOP) receptors. Experimental mono‐arthritis was induced by intra‐articular injection of complete Freunds adjuvant into the left hind knee joint. Intravenous (i.v.) administration of cebranopadol 0.8–8.0 &mgr;g/kg to rats 5 days after induction of arthritis elicited dose‐dependent increases in weight bearing on the affected limb. The quarter‐maximal effective dose (ED25) for this anti‐hypersensitive effect of cebranopadol was 1.6 &mgr;g/kg i.v. (95% confidence interval [CI]: 0.8, 1.6). The ED25 increased to 3.2 &mgr;g/kg i.v. (95% CI: 2.4, 4.0) following pretreatment with the selective NOP receptor antagonist J‐113397 and to 18.3 &mgr;g/kg i.v. (95% CI: 9.6, 146.0) following pretreatment with the MOP receptor antagonist naloxone (at intraperitoneal antagonist doses of 4.64 mg/kg and 1.0 mg/kg, respectively). The MOP receptor agonist morphine and the NOP receptor agonist Ro65–6570 also elicited increases in weight bearing on the affected limb. The anti‐hypersensitive effect of morphine 2.15 mg/kg i.v. was inhibited by naloxone but not by J‐113397. Conversely, the anti‐hypersensitive effect of Ro65–6570 0.464 mg/kg i.v. was inhibited by J‐113397 but not by naloxone. In conclusion, cebranopadol evoked potent anti‐hypersensitive efficacy in a rat model of arthritic pain, and this involved agonist activity at both the NOP and MOP receptors.

Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development

Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.