title: Modulation of l-α-lysophosphatidylinositol/GPR55 MAP kinase signalling by CB2 receptor agonists: identifying novel GPR55 inhibitors.
abstract: 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.
authors.forename: Sharon
authors.initials: S
authors.lastname: Anavi-Goffer
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Irving
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001643:Bridged Bicyclo Compounds; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; C524885:GPR55 protein, human; C573862:HU-910; D008024:Ligands; D008246:Lysophospholipids; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; C025449:lysophosphatidylinositol; C402416:HU 308