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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

A Novel Cannabinoid Peripheral Cannabinoid Receptor-Selective Inverse Agonist Blocks Leukocyte Recruitment in Vivo

Charles A. Lunn, Jay S. Fine, Alberto Rojas-Triana, James V. Jackson, Xuedong Fan, Ted T. Kung, Waldemar Gonsiorek, Martin A. Schwarz, Brian Lavey, Joseph A. Kozlowski, Satwant K. Narula, Daniel J. Lundell, R. William Hipkin and Loretta A. Bober
Journal of Pharmacology and Experimental Therapeutics February 2006, 316 (2) 780-788; DOI: https://doi.org/10.1124/jpet.105.093500
Charles A. Lunn
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Jay S. Fine
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Alberto Rojas-Triana
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James V. Jackson
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Xuedong Fan
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Ted T. Kung
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Waldemar Gonsiorek
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Martin A. Schwarz
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Brian Lavey
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Joseph A. Kozlowski
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Satwant K. Narula
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Daniel J. Lundell
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R. William Hipkin
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Loretta A. Bober
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Abstract

The expression of the cannabinoid peripheral cannabinoid receptor (CB2) receptor on peripheral immune cells suggests that compounds specific for CB2 might be effective anti-inflammatory agents. In this report, we present the initial biological profiling of a novel triaryl bis-sulfone, Sch.336 (N-[1(S)-[4-[[4-methoxy-2-[(4-methoxyphenyl)sulfonyl]phenyl]-sulfonyl]phenyl]ethyl]methanesulfonamide), which is selective for the human cannabinoid CB2 receptor (hCB2). Sch.336 is an inverse agonist at hCB2, as shown by its ability to decrease guanosine 5′-3-O-(thio)triphosphate (GTPγS) binding to membranes containing hCB2, by the ability of GTPγS to left-shift Sch.336 binding to hCB2 in these membranes, and by the compound's ability to increase forskolin-stimulated cAMP levels in CHO cells expressing hCB2. In these systems, Sch.336 displays a greater potency than that reported for the CB2-selective dihydropyrazole, SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1]heptan2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide). In vitro, Sch.336 impairs the migration of CB2-expressing recombinant cell lines to the cannabinoid agonist 2-arachidonylglycerol. In vivo, the compound impairs migration of cells to cannabinoid agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol]. Oral administration of the Sch.336 significantly inhibited leukocyte trafficking in several rodent in vivo models, induced either by specific chemokines or by antigen challenge. Finally, oral administration of Sch.336 blocked ovalbumin-induced lung eosinophilia in mice, a disease model for allergic asthma. We conclude that selective cannabinoid CB2 inverse agonists may serve as novel immunomodulatory agents in the treatment of a broad range of acute and chronic inflammatory disorders in which leukocyte recruitment is a hallmark of disease pathology.

Footnotes

  • doi:10.1124/jpet.105.093500.

  • ABBREVIATIONS: CB1, central cannabinoid receptor; CB2, peripheral cannabinoid receptor; Sch.336, N-[1(S)-[4-[[4-methoxy-2-[(4-methoxyphenyl)sulfonyl]phenyl]sulfonyl]phenyl]ethyl]methanesulfonamide; GTPγS, 5′-3-O-(thio)triphosphate; Sch.A, N-[1(S)-[4-[[4-methoxy-2-[(4-methoxyphenyl) sulfonyl]phenyl]sulfonyl]phenyl]ethyl]benzenemethanesulfonamide); Sch.B, N-[1(S)-[4-[[2-[(4-chlorophenyl)sulfonyl]-4-methoxyphenyl]sulfonyl]phenyl]ethyl]-2,2-dimethyl propanamide); CP55,940, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol; hCB2, human cannabinoid CB2 receptor; FBS, fetal bovine serum; BSA, bovine serum albumin; PBS, phosphate-buffered saline; mBSA, methylated BSA; HU210, (6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol; SR144528, N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide; SR141716A, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide; WIN55,212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate; 2-AG, 2-arachidonylglycerol; BAL, bronchoalveolar lavage.

    • Received August 3, 2005.
    • Accepted October 24, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 316 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 2
1 Feb 2006
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

A Novel Cannabinoid Peripheral Cannabinoid Receptor-Selective Inverse Agonist Blocks Leukocyte Recruitment in Vivo

Charles A. Lunn, Jay S. Fine, Alberto Rojas-Triana, James V. Jackson, Xuedong Fan, Ted T. Kung, Waldemar Gonsiorek, Martin A. Schwarz, Brian Lavey, Joseph A. Kozlowski, Satwant K. Narula, Daniel J. Lundell, R. William Hipkin and Loretta A. Bober
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 780-788; DOI: https://doi.org/10.1124/jpet.105.093500

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

A Novel Cannabinoid Peripheral Cannabinoid Receptor-Selective Inverse Agonist Blocks Leukocyte Recruitment in Vivo

Charles A. Lunn, Jay S. Fine, Alberto Rojas-Triana, James V. Jackson, Xuedong Fan, Ted T. Kung, Waldemar Gonsiorek, Martin A. Schwarz, Brian Lavey, Joseph A. Kozlowski, Satwant K. Narula, Daniel J. Lundell, R. William Hipkin and Loretta A. Bober
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 780-788; DOI: https://doi.org/10.1124/jpet.105.093500
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