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).

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