Cannabinoid CB(2)-selective inverse agonist protects against antigen-induced bone loss.
Work to improve the therapeutic properties of cannabinoid CB(2) receptor-selective inverse agonists has led to the development of Sch.036, an aryl substituted triaryl bis-sulfone with improved oral pharmacokinetic parameters. In this report, we show that this compound blocks in vivo trafficking of various leukocyte populations, a property consistent with other members of this chemical series. This CB(2)-selective compound also shows efficacy in leukocyte recruitment models when added in concert with suboptimal doses of selected anti-inflammatory agents, consistent with its unique function and indicative of its potential therapeutic utility. Finally, studies with Sch.036 show that this cannabinoid CB(2)-specific inverse agonist can ameliorate bone damage in a rat model of relapsing-remitting arthritis. This result suggests that a cannabinoid CB(2)-selective inverse agonist may help ameliorate a particularly harmful property of this inflammatory joint disease.
Lunn
Charles A
CA
New Lead Discovery, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. charles.lunn@spcorp.com
Fine
Jay
J
Rojas-Triana
Alberto
A
Jackson
James V
JV
Lavey
Brian
B
Kozlowski
Joseph A
JA
Hipkin
R William
RW
Lundell
Daniel J
DJ
Bober
Loretta
L
D000818:Animals; D000941:Antigens / Q000633:toxicity*; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001862:Bone Resorption / Q000139:chemically induced* / Q000517:prevention & control*; D002633:Chemotaxis / Q000187:drug effects; D004487:Edema / Q000188:drug therapy; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006968:Hypersensitivity, Delayed / Q000188:drug therapy / Q000276:immunology; D007202:Indicators and Reagents; D008024:Ligands; D008070:Lipopolysaccharides; D051379:Mice; D010998:Pleurisy / Q000139:chemically induced / Q000517:prevention & control; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
D000941:Antigens; D050071:Bone Density Conservation Agents; D007202:Indicators and Reagents; D008024:Ligands; D008070:Lipopolysaccharides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C526688:Sch 036; D013450:Sulfones; D016244:Guanosine 5'-O-(3-Thiotriphosphate)