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

Sharon Anavi-Goffer* (Corresponding Author), Andrew J. Irving, Ruth A. Ross

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)303–310
Number of pages8
JournalJournal of Basic and Clinical Physiology and Pharmacology
Volume27
Issue number3
Early online date18 Apr 2016
DOIs
Publication statusPublished - 1 May 2016

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Cannabinoid Receptor CB2
Phosphotransferases
Phosphorylation
Artificial Receptors
Ligands
Lipids
Cannabinoids
Structure-Activity Relationship
G-Protein-Coupled Receptors
HU 308
lysophosphatidylinositol

Keywords

  • AlphaScreen
  • cannabinoids
  • CB2 receptor-selective agonists
  • endocannabinoids
  • ERK1/2
  • GPR55

Cite this

@article{2e4d746078ad4e18b79dcd25145fb8ba,
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{\circledR} SureFire{\circledR} 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.",
keywords = "AlphaScreen, cannabinoids, CB2 receptor-selective agonists, endocannabinoids, ERK1/2, GPR55",
author = "Sharon Anavi-Goffer and Irving, {Andrew J.} and Ross, {Ruth A.}",
year = "2016",
month = "5",
day = "1",
doi = "10.1515/jbcpp-2015-0142",
language = "English",
volume = "27",
pages = "303–310",
journal = "Journal of Basic and Clinical Physiology and Pharmacology",
issn = "0792-6855",
publisher = "Walter de Gruyter & Co.",
number = "3",

}

TY - JOUR

T1 - Modulation of l-α-lysophosphatidylinositol/GPR55 MAP kinase signalling by CB2 receptor agonists

T2 - identifying novel GPR55 inhibitors

AU - Anavi-Goffer, Sharon

AU - Irving, Andrew J.

AU - Ross, Ruth A.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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.

AB - 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.

KW - AlphaScreen

KW - cannabinoids

KW - CB2 receptor-selective agonists

KW - endocannabinoids

KW - ERK1/2

KW - GPR55

U2 - 10.1515/jbcpp-2015-0142

DO - 10.1515/jbcpp-2015-0142

M3 - Article

VL - 27

SP - 303

EP - 310

JO - Journal of Basic and Clinical Physiology and Pharmacology

JF - Journal of Basic and Clinical Physiology and Pharmacology

SN - 0792-6855

IS - 3

ER -