![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication August 3, 2005.
Revised October 21, 2005.
Accepted for publication October 24, 2005.
The expression of the cannabinoid 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 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 GTP
S binding to membranes containing hCB2, by the ability of GTPS 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. 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 HU-210. 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.
Key words:
CB2 receptor, cannabinoid, chemotaxis, delayed type hypersensitivity, eosinophilia, inverse agonist
This article has been cited by other articles:
|
|
 |
|
  F. Montecucco, F. Burger, F. Mach, and S. Steffens CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1145 - H1155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. McHugh, C. Tanner, R. Mechoulam, R. G. Pertwee, and R. A. Ross Inhibition of Human Neutrophil Chemotaxis by Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct from CB1 and CB2 Mol. Pharmacol., February 1, 2008; 73(2): 441 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Karsak, E. Gaffal, R. Date, L. Wang-Eckhardt, J. Rehnelt, S. Petrosino, K. Starowicz, R. Steuder, E. Schlicker, B. Cravatt, et al. Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System Science, June 8, 2007; 316(5830): 1494 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Oka, J. Wakui, S. Ikeda, S. Yanagimoto, S. Kishimoto, M. Gokoh, M. Nasui, and T. Sugiura Involvement of the Cannabinoid CB2 Receptor and Its Endogenous Ligand 2-Arachidonoylglycerol in Oxazolone-Induced Contact Dermatitis in Mice J. Immunol., December 15, 2006; 177(12): 8796 - 8805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Gonsiorek, D. Hesk, S.-C. Chen, D. Kinsley, J. S. Fine, J. V. Jackson, L. A. Bober, G. Deno, H. Bian, J. Fossetta, et al. Characterization of Peripheral Human Cannabinoid Receptor (hCB2) Expression and Pharmacology Using a Novel Radioligand, [35S]Sch225336 J. Biol. Chem., September 22, 2006; 281(38): 28143 - 28151. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
