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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor

Murielle Rinaldi-Carmona, Francis Barth, José Millan, Jean-Marie Derocq, Pierre Casellas, Christian Congy, Didier Oustric, Martine Sarran, Monsif Bouaboula, Bernard Calandra, Marielle Portier, David Shire, Jean-Claude Brelière and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics February 1998, 284 (2) 644-650;
Murielle Rinaldi-Carmona
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Francis Barth
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José Millan
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Jean-Marie Derocq
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Pierre Casellas
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Christian Congy
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Didier Oustric
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Martine Sarran
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Monsif Bouaboula
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Bernard Calandra
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Marielle Portier
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David Shire
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Jean-Claude Brelière
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Gérard Le Fur
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Abstract

Based on both binding and functional data, this study introduces SR 144528 as the first, highly potent, selective and orally active antagonist for the CB2 receptor. This compound which displays subnanomolar affinity (Ki = 0.6 nM) for both the rat spleen and cloned human CB2 receptors has a 700-fold lower affinity (Ki = 400 nM) for both the rat brain and cloned human CB1 receptors. Furthermore it shows no affinity for any of the more than 70 receptors, ion channels or enzymes investigated (IC50 > 10 μM). In vitro, SR 144528 antagonizes the inhibitory effects of the cannabinoid receptor agonist CP 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines permanently expressing the h CB2 receptor (EC50 = 10 nM) but not in cells expressing the h CB1 (no effect at 10 μM). Furthermore, SR 144528 is able to selectively block the mitogen-activated protein kinase activity induced by CP 55,940 in cell lines expressing h CB2 (IC50 = 39 nM) whereas in cells expressing h CB1 an IC50 value of more than 1 μM is found. In addition, SR 144528 is shown to antagonize the stimulating effects of CP 55,940 on human tonsillar B-cell activation evoked by cross-linking of surface Igs (IC50 = 20 nM). In vivo, after oral administration SR 144528 totally displaced theex vivo [3H]-CP 55,940 binding to mouse spleen membranes (ED50 = 0.35 mg/kg) with a long duration of action. In contrast, after the oral route it does not interact with the cannabinoid receptor expressed in the mouse brain (CB1). It is expected that SR 144528 will provide a powerful tool to investigate the in vivo functions of the cannabinoid system in the immune response.

Footnotes

  • Send reprint requests to: Dr. Murielle Rinaldi-Carmona: Sanofi Recherche, 371 rue du Professeur J Blayac, 34184 Montpellier Cédex, France.

  • Abbreviations:
    anti-Ig
    anti-human surface immunoglobulins
    BSA
    bovine serum albumin
    CB1
    central cannabinoid receptor
    CB2
    peripheral cannabinoid receptor
    h CB1
    human central cannabinoid receptor
    h CB2
    human peripheral cannabinoid receptor
    CHO
    Chinese hamster ovary
    IBMX
    isobutylmethylxanthine
    i.c.v.
    intracerebral ventricular
    fMAPK
    mitogen-activated protein kinase
    PBS
    phosphate-buffered saline
    PTX
    pertussis toxin
    Δ9-THC
    tetrahydrocannabinol
    Tris
    Tris-(hydroxymethyl)-amino-methane
    • Received July 25, 1997.
    • Accepted October 13, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 2
1 Feb 1998
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor

Murielle Rinaldi-Carmona, Francis Barth, José Millan, Jean-Marie Derocq, Pierre Casellas, Christian Congy, Didier Oustric, Martine Sarran, Monsif Bouaboula, Bernard Calandra, Marielle Portier, David Shire, Jean-Claude Brelière and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 644-650;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor

Murielle Rinaldi-Carmona, Francis Barth, José Millan, Jean-Marie Derocq, Pierre Casellas, Christian Congy, Didier Oustric, Martine Sarran, Monsif Bouaboula, Bernard Calandra, Marielle Portier, David Shire, Jean-Claude Brelière and Gérard Le Fur
Journal of Pharmacology and Experimental Therapeutics February 1, 1998, 284 (2) 644-650;
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