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

Wolfgang Schuehly, Juan Manuel Viveros Paredes, Jonas Kleyer, Antje Huefner, Sharon Anavi-Goffer, Stefan Raduner, Karl-Heinz Altmann, Jürg Gertsch* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Citations (Scopus)


The cannabinoid CB2 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 CB2 receptor-selective antiosteoclastogenic lead structure (Ki < 50 nM). Intriguingly, MH triggers a simultaneous Gi inverse agonist response and a strong CB2 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 CB2 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 CB2 receptor-selective scaffold that exhibits a novel type of functional heterogeneity.
Original languageEnglish
Pages (from-to)1053-1064
Number of pages12
JournalChemistry & Biology
Issue number8
Early online date25 Aug 2011
Publication statusPublished - 26 Aug 2011


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