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 p...
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| creator | Linz, Klaus Christoph, Thomas Tzschentke, Thomas M. Koch, Thomas Schiene, Klaus Gautrois, Michael Schröder, Wolfgang Kögel, Babette Y. Beier, Horst Englberger, Werner Schunk, Stefan De Vry, Jean Jahnel, Ulrich Frosch, Stefanie |
| description | 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. |
| doi_str_mv | 10.1124/jpet.114.213694 |
| format | Article |
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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.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.114.213694</identifier><identifier>PMID: 24713140</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Analgesics, Opioid - administration & dosage ; Analgesics, Opioid - adverse effects ; Analgesics, Opioid - pharmacology ; Analgesics, Opioid - therapeutic use ; Animals ; Arthritis, Experimental - complications ; Arthritis, Experimental - drug therapy ; Arthritis, Experimental - metabolism ; Behavior, Animal - drug effects ; Bone Neoplasms - complications ; Bone Neoplasms - drug therapy ; Bone Neoplasms - metabolism ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; CHO Cells ; Cricetinae ; Cricetulus ; Female ; Indoles - administration & dosage ; Indoles - adverse effects ; Indoles - pharmacology ; Indoles - therapeutic use ; Male ; Nociceptin ; Opioid Peptides - agonists ; Pain - drug therapy ; Pain - etiology ; Pain - metabolism ; Polyneuropathies - complications ; Polyneuropathies - drug therapy ; Polyneuropathies - metabolism ; Protein Binding ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Opioid - agonists ; Rotarod Performance Test ; Spiro Compounds - administration & dosage ; Spiro Compounds - adverse effects ; Spiro Compounds - pharmacology ; Spiro Compounds - therapeutic use</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2014-06, Vol.349 (3), p.535-548</ispartof><rights>2014 American Society for Pharmacology and Experimental Therapeutics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c308t-a3ffccd8e0ff80ed91826271ee51afae29a286ee3639b27a9aee6a58e883012d3</citedby><cites>FETCH-LOGICAL-c308t-a3ffccd8e0ff80ed91826271ee51afae29a286ee3639b27a9aee6a58e883012d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24713140$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Linz, Klaus</creatorcontrib><creatorcontrib>Christoph, Thomas</creatorcontrib><creatorcontrib>Tzschentke, Thomas M.</creatorcontrib><creatorcontrib>Koch, Thomas</creatorcontrib><creatorcontrib>Schiene, Klaus</creatorcontrib><creatorcontrib>Gautrois, Michael</creatorcontrib><creatorcontrib>Schröder, Wolfgang</creatorcontrib><creatorcontrib>Kögel, Babette Y.</creatorcontrib><creatorcontrib>Beier, Horst</creatorcontrib><creatorcontrib>Englberger, Werner</creatorcontrib><creatorcontrib>Schunk, Stefan</creatorcontrib><creatorcontrib>De Vry, Jean</creatorcontrib><creatorcontrib>Jahnel, Ulrich</creatorcontrib><creatorcontrib>Frosch, Stefanie</creatorcontrib><title>Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>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.</description><subject>Analgesics, Opioid - administration & dosage</subject><subject>Analgesics, Opioid - adverse effects</subject><subject>Analgesics, Opioid - pharmacology</subject><subject>Analgesics, Opioid - therapeutic use</subject><subject>Animals</subject><subject>Arthritis, Experimental - complications</subject><subject>Arthritis, Experimental - drug therapy</subject><subject>Arthritis, Experimental - metabolism</subject><subject>Behavior, Animal - drug effects</subject><subject>Bone Neoplasms - complications</subject><subject>Bone Neoplasms - drug therapy</subject><subject>Bone Neoplasms - metabolism</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Female</subject><subject>Indoles - administration & dosage</subject><subject>Indoles - adverse effects</subject><subject>Indoles - pharmacology</subject><subject>Indoles - therapeutic use</subject><subject>Male</subject><subject>Nociceptin</subject><subject>Opioid Peptides - agonists</subject><subject>Pain - drug therapy</subject><subject>Pain - etiology</subject><subject>Pain - metabolism</subject><subject>Polyneuropathies - complications</subject><subject>Polyneuropathies - drug therapy</subject><subject>Polyneuropathies - metabolism</subject><subject>Protein Binding</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Wistar</subject><subject>Receptors, Opioid - agonists</subject><subject>Rotarod Performance Test</subject><subject>Spiro Compounds - administration & dosage</subject><subject>Spiro Compounds - adverse effects</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spiro Compounds - therapeutic use</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kF9LwzAUxYMobk6ffZN8gW751y71rQynwnBT9Llkye3M6JKS1MG-vS1V33y6h8PvHC4HoVtKppQyMds30HZKTBnlWS7O0JimjCaEEn6OxoQwlvA0S0foKsY9IVSIjF-iERNzyqkgY6QWsA3K-UYZX9_jAr_4I9R441twLS6cqncQre5sbTU0rXWzdWg-lbMOL1_xprcMYOUMXjfWW4PfoOd8wMXOOxvba3RRqTrCzc-doI_lw_viKVmtH58XxSrRnMg2UbyqtDYSSFVJAiankmVsTgFSqioFLFdMZgA84_mWzVWuADKVSpCSE8oMn6DZ0KuDjzFAVTbBHlQ4lZSU_VhlP1anRDmM1SXuhkTztT2A-eN_1-mAfACg-_toIZRRW3AajA2g29J4-2_5N6G4efY</recordid><startdate>201406</startdate><enddate>201406</enddate><creator>Linz, Klaus</creator><creator>Christoph, Thomas</creator><creator>Tzschentke, Thomas M.</creator><creator>Koch, Thomas</creator><creator>Schiene, Klaus</creator><creator>Gautrois, Michael</creator><creator>Schröder, Wolfgang</creator><creator>Kögel, Babette Y.</creator><creator>Beier, Horst</creator><creator>Englberger, Werner</creator><creator>Schunk, Stefan</creator><creator>De Vry, Jean</creator><creator>Jahnel, Ulrich</creator><creator>Frosch, Stefanie</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>201406</creationdate><title>Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist</title><author>Linz, Klaus ; Christoph, Thomas ; Tzschentke, Thomas M. ; Koch, Thomas ; Schiene, Klaus ; Gautrois, Michael ; Schröder, Wolfgang ; Kögel, Babette Y. ; Beier, Horst ; Englberger, Werner ; Schunk, Stefan ; De Vry, Jean ; Jahnel, Ulrich ; Frosch, Stefanie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c308t-a3ffccd8e0ff80ed91826271ee51afae29a286ee3639b27a9aee6a58e883012d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Analgesics, Opioid - administration & dosage</topic><topic>Analgesics, Opioid - adverse effects</topic><topic>Analgesics, Opioid - pharmacology</topic><topic>Analgesics, Opioid - therapeutic use</topic><topic>Animals</topic><topic>Arthritis, Experimental - complications</topic><topic>Arthritis, Experimental - drug therapy</topic><topic>Arthritis, Experimental - metabolism</topic><topic>Behavior, Animal - drug effects</topic><topic>Bone Neoplasms - complications</topic><topic>Bone Neoplasms - drug therapy</topic><topic>Bone Neoplasms - metabolism</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Female</topic><topic>Indoles - administration & dosage</topic><topic>Indoles - adverse effects</topic><topic>Indoles - pharmacology</topic><topic>Indoles - therapeutic use</topic><topic>Male</topic><topic>Nociceptin</topic><topic>Opioid Peptides - agonists</topic><topic>Pain - drug therapy</topic><topic>Pain - etiology</topic><topic>Pain - metabolism</topic><topic>Polyneuropathies - complications</topic><topic>Polyneuropathies - drug therapy</topic><topic>Polyneuropathies - metabolism</topic><topic>Protein Binding</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Wistar</topic><topic>Receptors, Opioid - agonists</topic><topic>Rotarod Performance Test</topic><topic>Spiro Compounds - administration & dosage</topic><topic>Spiro Compounds - adverse effects</topic><topic>Spiro Compounds - pharmacology</topic><topic>Spiro Compounds - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Linz, Klaus</creatorcontrib><creatorcontrib>Christoph, Thomas</creatorcontrib><creatorcontrib>Tzschentke, Thomas M.</creatorcontrib><creatorcontrib>Koch, Thomas</creatorcontrib><creatorcontrib>Schiene, Klaus</creatorcontrib><creatorcontrib>Gautrois, Michael</creatorcontrib><creatorcontrib>Schröder, Wolfgang</creatorcontrib><creatorcontrib>Kögel, Babette Y.</creatorcontrib><creatorcontrib>Beier, Horst</creatorcontrib><creatorcontrib>Englberger, Werner</creatorcontrib><creatorcontrib>Schunk, Stefan</creatorcontrib><creatorcontrib>De Vry, Jean</creatorcontrib><creatorcontrib>Jahnel, Ulrich</creatorcontrib><creatorcontrib>Frosch, Stefanie</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Linz, Klaus</au><au>Christoph, Thomas</au><au>Tzschentke, Thomas M.</au><au>Koch, Thomas</au><au>Schiene, Klaus</au><au>Gautrois, Michael</au><au>Schröder, Wolfgang</au><au>Kögel, Babette Y.</au><au>Beier, Horst</au><au>Englberger, Werner</au><au>Schunk, Stefan</au><au>De Vry, Jean</au><au>Jahnel, Ulrich</au><au>Frosch, Stefanie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2014-06</date><risdate>2014</risdate><volume>349</volume><issue>3</issue><spage>535</spage><epage>548</epage><pages>535-548</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract>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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24713140</pmid><doi>10.1124/jpet.114.213694</doi><tpages>14</tpages></addata></record> |
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| subjects | Analgesics, Opioid - administration & dosage Analgesics, Opioid - adverse effects Analgesics, Opioid - pharmacology Analgesics, Opioid - therapeutic use Animals Arthritis, Experimental - complications Arthritis, Experimental - drug therapy Arthritis, Experimental - metabolism Behavior, Animal - drug effects Bone Neoplasms - complications Bone Neoplasms - drug therapy Bone Neoplasms - metabolism Cell Membrane - drug effects Cell Membrane - metabolism CHO Cells Cricetinae Cricetulus Female Indoles - administration & dosage Indoles - adverse effects Indoles - pharmacology Indoles - therapeutic use Male Nociceptin Opioid Peptides - agonists Pain - drug therapy Pain - etiology Pain - metabolism Polyneuropathies - complications Polyneuropathies - drug therapy Polyneuropathies - metabolism Protein Binding Radioligand Assay Rats Rats, Sprague-Dawley Rats, Wistar Receptors, Opioid - agonists Rotarod Performance Test Spiro Compounds - administration & dosage Spiro Compounds - adverse effects Spiro Compounds - pharmacology Spiro Compounds - therapeutic use |
| title | Cebranopadol: A Novel Potent Analgesic Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist |
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