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NEUROPHARMACOLOGY
GlaxoSmithKline Pharmaceuticals, Departments of Neurobiology Research (P.F.Z., G.P., M.S., M.G., C.F., P.P., M.A.S.) and Medicinal Chemistry (S.R., G.A.M.G.), Milan, Italy; and Neurology Centre of Excellence for Drug Discovery, New Frontiers Science Park, Harlow, United Kingdom
(–)-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 Ki = 0.33 nM), selectivity versus µ-(174-fold), 
-(6391-fold), and 
(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 [ED50 = 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 (ED50 = 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.
Address correspondence to: Dr. Mark A. Scheideler, P.O. Box 16, 10325 Kensington Pkwy., Kensington, MD 20895. E-mail: mark.scheideler{at}att.net
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