Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists.
Evidence has emerged suggesting a role for the cannabinoid CB2 receptor in immune cell motility. This provides a rationale for a novel and generalized immunoregulatory role for cannabinoid CB2 receptor-specific compounds. In support of this possibility, we will review the biology of a class of cannabinoid CB2 receptor-specific inverse agonist, the triaryl bis-sulfones. We will show that one candidate, Sch.414319, is potent and selective for the cannabinoid CB2 receptor, based on profiling studies using biochemical assays for 45 enzymes and 80 G-protein coupled receptors and ion channels. We will describe initial mechanistic studies using this optimized triaryl bis-sulfone, showing that the compound exerts a broad effect on cellular protein phosphorylations in human monocytes. This profile includes the down regulation of a required phosphorylation of the monocyte-specific actin bundling protein L-plastin. We suggest that this observation may provide a mechanism for the observed activity of Sch.414319 in vivo. Our continued analysis of the in vivo efficacy of this compound in diverse disease models shows that Sch.414319 is a potent modulator of immune cell mobility in vivo, can modulate bone damage in antigen-induced mono-articular arthritis in the rat, and is uniquely potent at blocking experimental autoimmune encephalomyelitis in the rat.
Lunn
C A
CA
Department of New Lead Discovery, Schering-Plough Research Institute, Kenilworth, NJ, USA. charles.lunn@spcorp.com
Reich
E-P
EP
Fine
J S
JS
Lavey
B
B
Kozlowski
J A
JA
Hipkin
R W
RW
Lundell
D J
DJ
Bober
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology
D043885:Receptor, Cannabinoid, CB2; D013450:Sulfones