A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo.
The expression of the cannabinoid peripheral cannabinoid receptor (CB(2)) receptor on peripheral immune cells suggests that compounds specific for CB(2) 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 CB(2) receptor (hCB(2)). Sch.336 is an inverse agonist at hCB(2), as shown by its ability to decrease guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding to membranes containing hCB(2), by the ability of GTPgammaS to left-shift Sch.336 binding to hCB(2) in these membranes, and by the compound's ability to increase forskolin-stimulated cAMP levels in CHO cells expressing hCB(2). In these systems, Sch.336 displays a greater potency than that reported for the CB(2)-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 CB(2)-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 CB(2) 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.
Lunn
Charles A
CA
New Lead Discovery, Schering-Plough Research Institute, Kenilworth, New Jersey, USA. charles.lunn@spcorp.com.
Fine
Jay S
JS
Rojas-Triana
Alberto
A
Jackson
James V
JV
Fan
Xuedong
X
Kung
Ted T
TT
Gonsiorek
Waldemar
W
Schwarz
Martin A
MA
Lavey
Brian
B
Kozlowski
Joseph A
JA
Narula
Satwant K
SK
Lundell
Daniel J
DJ
Hipkin
R William
RW
Bober
Loretta A
LA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D001892:Camphanes / Q000494:pharmacology* / Q000627:therapeutic use; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D011657:Pulmonary Eosinophilia / Q000188:drug therapy; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000096:biosynthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001892:Camphanes; D002186:Cannabinoids; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP