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INFLAMMATION AND IMMUNOPHARMACOLOGY

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

New Lead Discovery (C.A.L.) and Departments of Inflammation and Infectious Diseases (J.S.F., A.R.-T., J.V.J., X.F., W.G., M.A.S., S.K.N., D.J.L., R.W.H., L.A.B.), Allergy (T.T.K.), and Chemistry (B.L., J.A.K.), Schering-Plough Research Institute, Kenilworth, New Jersey

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 (GTPS) 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 (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.

Address correspondence to: Dr. Charles A. Lunn, Department of New Lead Discovery, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033. E-mail: charles.lunn{at}spcorp.com

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