Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists

Abstract

The cannabinoid CB(2) receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4'-O-methylhonokiol (MH) is a CB(2) receptor-selective antiosteoclastogenic lead structure (K(i) < 50 nM). Intriguingly, MH triggers a simultaneous G(i) inverse agonist response and a strong CB(2) receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB(2) receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB(2) receptor-selective scaffold that exhibits a novel type of functional heterogeneity.

Functional Selectivity in CB2 Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB2 Ligands

“…These observations emphasize that the concept of functional selectivity also applies to inverse agonists, in that both compounds are similarly effective inverse agonists in guanosine 5Ј-O-(3-thio)triphosphate binding assays (Ross et al, 1999). These data also support the differences (Schuehly et al, 2011) observed between SR144528 and AM630. However, the lack of effect of AM630 on CB 2 surface levels seems to contradict the Grimsey et al (2011) report, for unclear reasons.…”

“…Each ligand differed in its rank order of potency in the three assays despite similar efficacies. Schuehly et al (2011) recently described a case of functional selectivity of CB 2 ligands. AM630 displayed inverse agonist/antagonist actions on CB 2 -mediated inhibition of cAMP production and was silent in its effects on intracellular calcium transients.…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Previous studies revealed that 4-O-methylhonokiol potently inhibited neuroinflammatory responses and was associated with cognitive enhancement in AD animal models. The antiinflammatory activity was mediated by diminishing NF-jB signaling pathway (Lee et al 2012a (Schuehly et al 2011). They suggest that the effects of the compound on CB 2 receptors are associated with anti-neuroinflammatory effects, since the receptors are primarily associated with a broad range of inflammatory processes (Gertsch & Anavi-Goffer 2012).…”

CB2Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

“…However, activation of CB 2 receptors in the BV2 microglial cell line inhibits adenylyl cyclase (Franklin et al, 2003). A particularly interesting example is the natural product 49-O-methylhonokiol, which shows inverse agonism for cAMP production and agonism for release of intracellular calcium (Schuehly et al, 2011).…”