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Research ArticleNEUROPHARMACOLOGY

SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization

Murielle Rinaldi-Carmona, Francis Barth, Christian Congy, Serge Martinez, Didier Oustric, Alain Pério, Martine Poncelet, Jeanne Maruani, Michèle Arnone, Olivier Finance, Philippe Soubrié and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 905-914; DOI: https://doi.org/10.1124/jpet.104.067884
Murielle Rinaldi-Carmona
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Francis Barth
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Christian Congy
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Serge Martinez
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Didier Oustric
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Alain Pério
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Martine Poncelet
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Jeanne Maruani
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Michèle Arnone
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Olivier Finance
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Philippe Soubrié
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Gérard Le Fur
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Abstract

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (Ki = 0.56 and 3.5 nM) for both the rat brain and human CB1 recombinant receptors, respectively. It has low affinity (Ki = 400 nM) for both the rat spleen and human CB2 receptors. Furthermore, it shows no affinity for any of the over 100 targets investigated (IC50 > 1 μM). In vitro, SR147778 antagonizes the inhibitory effects of CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] on both the mouse vas deferens contractions (pA2 value = 8.1) and on forskolin-stimulated adenylyl cyclase activity in the U373 MG cell lines (pA2 value = 8.2) but not in Chinese hamster ovary (CHO) cells permanently expressing the human peripheral cannabinoid receptor (hCB2). SR147778 is able to block the mitogen-activated protein kinase activity induced by CP 55,940 in the CHO cell line expressing human brain cannabinoid receptor (IC50 = 9.6 nM) but was inactive in cells expressing hCB2. After oral administration, SR147778 displaced the ex vivo [3H]-CP 55,940 binding to mouse brain membranes (ED50 = 3.8 mg/kg) with a long duration of action, whereas it did not interact with the CB2 receptor expressed in the mouse spleen. Using different routes of administration, SR147778 (0.3–3 mg/kg) is shown to antagonize pharmacological effects (hypothermia, analgesia, and gastrointestinal transit) induced by R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinyl}methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone in mice. Finally, per se, SR147778 (0.3–10 mg/kg) is able to reduce ethanol or sucrose consumption in mice and rats and food intake in fasted and nondeprived rats.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.067884.

  • ABBREVIATIONS: Δ9-THC, tetrahydrocannabinol; SR147778, 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide; CP 55,940, (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol; SIP, schedule-induced ethanol polydipsia; CHO, Chinese hamster ovary; hCB1, human brain cannabinoid receptor; hCB2, human peripheral cannabinoid receptor; PBS, phosphate-buffered saline; PTX, pertussis toxin; MAPK, mitogen-activated protein kinase; ANOVA, analysis of variance; CL, confidence limit; RO20-1724, 4-[(3-butoxy-4-methoxyphenyl)methyl]2-imidazolidinone; JWH133, (6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran; WIN55212-2, R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinyl}methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone; SR141716, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, AEA, arachidonyl ethanolamide.

    • Received March 3, 2004.
    • Accepted May 3, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization
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Research ArticleNEUROPHARMACOLOGY

SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization

Murielle Rinaldi-Carmona, Francis Barth, Christian Congy, Serge Martinez, Didier Oustric, Alain Pério, Martine Poncelet, Jeanne Maruani, Michèle Arnone, Olivier Finance, Philippe Soubrié and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 905-914; DOI: https://doi.org/10.1124/jpet.104.067884

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Research ArticleNEUROPHARMACOLOGY

SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization

Murielle Rinaldi-Carmona, Francis Barth, Christian Congy, Serge Martinez, Didier Oustric, Alain Pério, Martine Poncelet, Jeanne Maruani, Michèle Arnone, Olivier Finance, Philippe Soubrié and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 905-914; DOI: https://doi.org/10.1124/jpet.104.067884
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