Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling

Schofield, ZV; Croker, D; Robertson, AAB; Massey, NL; Donovan, C; Tee, E; Edwards, D; Woodruff, TM; Halai, R; Hansbro, PM; Cooper, MA

Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling

Schofield, ZV Croker, D Robertson, AAB

Massey, NL Donovan, C Tee, E Edwards, D Woodruff, TM

Halai, R Hansbro, PM

Cooper, MA

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Publication Type:: Journal Article
Citation:: Scientific Reports, 2018, 8 (1)
Issue Date:: 2018-12-01

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Field	Value	Language
dc.contributor.author	Schofield, ZV	en_US
dc.contributor.author	Croker, D	en_US
dc.contributor.author	Robertson, AAB https://orcid.org/0000-0002-9652-8357	en_US
dc.contributor.author	Massey, NL	en_US
dc.contributor.author	Donovan, C	en_US
dc.contributor.author	Tee, E	en_US
dc.contributor.author	Edwards, D	en_US
dc.contributor.author	Woodruff, TM https://orcid.org/0000-0003-1382-911X	en_US
dc.contributor.author	Halai, R	en_US
dc.contributor.author	Hansbro, PM https://orcid.org/0000-0002-4741-3035	en_US
dc.contributor.author	Cooper, MA https://orcid.org/0000-0003-3147-3460	en_US
dc.date.available	2018-10-30	en_US
dc.date.issued	2018-12-01	en_US
dc.identifier.citation	Scientific Reports, 2018, 8 (1)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/129160
dc.description.abstract	© 2018, The Author(s). Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture (R/S) and its constituents (R-) and (S-) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate. Calcium ions (Ca2+), phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) and cyclic adenosine monophosphate (cAMP) were measured. R/S-4CMTB is a functionally selective ago-allosteric ligand that enhances Ca2+ response to acetate. Both R/S-4CMTB and S-4CMTB are more potent activators of pERK1/2 and inhibitors of forskolin-induced cAMP than acetate. S-4CMTB increased neutrophil infiltration in intestinal ischemia reperfusion injury (IRI). 2CTAP inhibited constitutive Ca2+ levels, antagonised acetate-induced pERK1/2 and prevented damage following IRI. This study characterises enantiomers of functionally selective ligands for FFA2 in cells stably expressing hFFA2. It highlights the novel roles of selective FFA2 enantiomers 4CMTB and 2CTAP on Ca2+, pERK1/2 and cAMP and their roles as allosteric modulators which, may assist in efforts to design novel therapeutic agents for FFA2-driven inflammatory diseases.	en_US
dc.relation.ispartof	Scientific Reports	en_US
dc.relation.isbasedon	10.1038/s41598-018-36242-1	en_US
dc.subject.mesh	CHO Cells	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Cricetulus	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Mitogen-Activated Protein Kinase 1	en_US
dc.subject.mesh	Mitogen-Activated Protein Kinase 3	en_US
dc.subject.mesh	Fatty Acids, Volatile	en_US
dc.subject.mesh	Receptors, Cell Surface	en_US
dc.subject.mesh	Cyclic AMP	en_US
dc.subject.mesh	Ligands	en_US
dc.subject.mesh	MAP Kinase Signaling System	en_US
dc.subject.mesh	Second Messenger Systems	en_US
dc.title	Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	8	en_US
utslib.for	0305 Organic Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	8	en_US

Abstract:

© 2018, The Author(s). Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture (R/S) and its constituents (R-) and (S-) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate. Calcium ions (Ca2+), phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) and cyclic adenosine monophosphate (cAMP) were measured. R/S-4CMTB is a functionally selective ago-allosteric ligand that enhances Ca2+ response to acetate. Both R/S-4CMTB and S-4CMTB are more potent activators of pERK1/2 and inhibitors of forskolin-induced cAMP than acetate. S-4CMTB increased neutrophil infiltration in intestinal ischemia reperfusion injury (IRI). 2CTAP inhibited constitutive Ca2+ levels, antagonised acetate-induced pERK1/2 and prevented damage following IRI. This study characterises enantiomers of functionally selective ligands for FFA2 in cells stably expressing hFFA2. It highlights the novel roles of selective FFA2 enantiomers 4CMTB and 2CTAP on Ca2+, pERK1/2 and cAMP and their roles as allosteric modulators which, may assist in efforts to design novel therapeutic agents for FFA2-driven inflammatory diseases.

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http://hdl.handle.net/10453/129160