Modification of nociception and morphine tolerance by the selective opiate receptor-like orphan receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)

J Pharmacol Exp Ther. 2004 Feb;308(2):454-61. doi: 10.1124/jpet.103.055848. Epub 2003 Oct 30.


(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cycloheptanes / pharmacology*
  • Cycloheptanes / therapeutic use
  • Drug Tolerance / physiology*
  • Humans
  • Morphine / adverse effects*
  • Morphine / therapeutic use
  • Narcotic Antagonists*
  • Nociceptin Receptor
  • Pain / drug therapy
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Receptors, Opioid


  • Cycloheptanes
  • Narcotic Antagonists
  • Piperidines
  • Receptors, Opioid
  • cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol
  • Morphine
  • Nociceptin Receptor