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

Sharon Anavi-Goffer; Andrew J. Irving; Ruth A. Ross

doi:10.1515/jbcpp-2015-0142

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 journal › Article › peer-review

6 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 language	English
Pages (from-to)	303–310
Number of pages	8
Journal	Journal of Basic and Clinical Physiology and Pharmacology
Volume	27
Issue number	3
Early online date	18 Apr 2016
DOIs	https://doi.org/10.1515/jbcpp-2015-0142
Publication status	Published - 1 May 2016

Keywords

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

Access to Document

10.1515/jbcpp-2015-0142Licence: Unspecified

Cite this

Modulation of l-α-lysophosphatidylinositol/GPR55 MAP kinase signalling by CB2 receptor agonists: identifying novel GPR55 inhibitors. / Anavi-Goffer, Sharon (Corresponding Author); Irving, Andrew J.; Ross, Ruth A.
In: Journal of Basic and Clinical Physiology and Pharmacology, Vol. 27, No. 3, 01.05.2016, p. 303–310.

Research output: Contribution to journal › Article › peer-review

@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{\textregistered} SureFire{\textregistered} 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 = may,

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

SN - 0792-6855

VL - 27

SP - 303

EP - 310

JO - Journal of Basic and Clinical Physiology and Pharmacology

JF - Journal of Basic and Clinical Physiology and Pharmacology

IS - 3

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this