Abstract
(–)-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), δ-(6391-fold), and κ (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.
Footnotes
-
DOI: 10.1124/jpet.103.055848.
-
ABBREVIATIONS: ORL, opiate receptor-like; DAMGO, d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; DPDPE, [d-Pen2,d-Pen5]-enkephalin; hMOR, human μ-opioid receptor; hDOR, human δ-opioid receptor; hKOR, human κ-opioid receptor; CHO, Chinese hamster ovary; FBS, fetal bovine serum; HEK, human embryonic kidney; RGS, regulator of G protein signaling; SB-612111, (–)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; UFP-101, [N-Phe1,Arg14,Lys15]N/OFQ-NH2; JTC-801, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide monohydrochloride; J-113397, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazole-2-one; U-69593, [(+)-(5α,7α,8b)-(+)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide]; BRL 52656, S(–)-2-(1-pyrrolidinylmethyl)-1-(4-trifluoromethylphenyl)acetyl piperidine hydrochloride; RX 821002, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)4,5-dihydro-1H-imidazole.
- Received June 17, 2003.
- Accepted October 16, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
Log in using your username and password
Purchase access
In this issue
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)
