Biology and therapeutic potential of cannabinoid CB2receptor inverse agonists

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Abstract
Evidence has emerged suggesting a role for the cannabinoid CB2receptor in immune cell motility. This provides a rationale for a novel and generalized immunoregulatory role for cannabinoid CB2receptor‐specific compounds. In support of this possibility, we will review the biology of a class of cannabinoid CB2receptor—specific inverse agonist, the triaryl bis‐sulfones. We will show that one candidate, Sch.414319, is potent and selective for the cannabinoid CB2receptor, 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.414319in vivo. Our continued analysis of thein vivoefficacy of this compound in diverse disease models shows that Sch.414319 is a potent modulator of immune cell mobilityin 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.British Journal of Pharmacology(2008)153, 226–239; doi:10.1038/sj.bjp.0707480; published online 1 October 2007