Modulation of l-α-lysophosphatidylinositol/GPR55 MAP kinase signalling by CB2 receptor agonists: identifying novel GPR55 inhibitors.

BACKGROUND: GPR55 is a lipid-sensing G protein-coupled receptor that is activated by the endogenous lipid l-α-lysophosphatidylinositol (LPI) and can be modulated by certain cannabinoid ligands.

METHODS: In this study we investigated the GPR55 activity of four synthetic CB2 receptor agonists using the AlphaScreen® SureFire® assay.

RESULTS: Here we show that the CB2 receptor-selective agonists HU-308, HU-433 and HU-910 do not promote GPR55-mediated ERK1/2 phosphorylation up to a concentration of 3 μM. However, LPI-induced ERK1/2 phosphorylation is inhibited by the (-)-enantiomer of HU-308, designated HU-433, whereas HU-308 has no effect on LPI activity. The carboxylic analogue of HU-910, designated HU-914, potently inhibits LPI-induced ERK1/2 phosphorylation; however, HU-914 was less effective, with potential biphasic effects.

CONCLUSIONS: This structure-activity-relationship study has identified novel ligands which act both as CB2 receptor agonists and GPR55 modulators and related compounds that lack GPR55 activity.