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.
Departments of Preclinical Drug Safety (K.L.), Global Preclinical Drug Development (S.F.), Global Preclinical Research and Development (U.J.), Pain Pharmacology (T.C., T.M.T., K.S., B.Y.K., J.D.V.), Molecular Pharmacology (T.K., W.E.), Translational Science (W.S.), Pharmacokinetics (M.G., H.B.), and Medicinal Chemistry (S.S.), Grünenthal GmbH, Aachen, Germany.
Klaus
K
Linz
Thomas
T
Christoph
Thomas M
TM
Tzschentke
Thomas
T
Koch
Klaus
K
Schiene
Michael
M
Gautrois
Wolfgang
W
Schröder
Babette Y
BY
Kögel
Horst
H
Beier
Werner
W
Englberger
Stefan
S
Schunk
Jean
J
De Vry
Ulrich
U
Jahnel
Stefanie
S
Frosch
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018847:Opioid Peptides / Q000819:agonists*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D011115:Polyneuropathies / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D045442:Rotarod Performance Test; D013141:Spiro Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000097629:Nociceptin
D000701:Analgesics, Opioid; D007211:Indoles; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000097629:Nociceptin; C000589289:6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro(cyclohexane-1,1'(3'H)-pyrano(3,4-b)indol)-4-amine