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

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)bu...

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Autores principales: Schofield, Zoe V., Croker, Daniel, Robertson, Avril A. B., Massey, Nicholas L., Donovan, Chantal, Tee, Ernest, Edwards, David, Woodruff, Trent M., Halai, Reena, Hansbro, Philip M., Cooper, Matthew A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292860/
https://www.ncbi.nlm.nih.gov/pubmed/30546040
http://dx.doi.org/10.1038/s41598-018-36242-1
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author Schofield, Zoe V.
Croker, Daniel
Robertson, Avril A. B.
Massey, Nicholas L.
Donovan, Chantal
Tee, Ernest
Edwards, David
Woodruff, Trent M.
Halai, Reena
Hansbro, Philip M.
Cooper, Matthew A.
author_facet Schofield, Zoe V.
Croker, Daniel
Robertson, Avril A. B.
Massey, Nicholas L.
Donovan, Chantal
Tee, Ernest
Edwards, David
Woodruff, Trent M.
Halai, Reena
Hansbro, Philip M.
Cooper, Matthew A.
author_sort Schofield, Zoe V.
collection PubMed
description 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 (Ca(2+)), 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 Ca(2+) 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 Ca(2+) 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 Ca(2+), 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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spelling pubmed-62928602018-12-21 Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling Schofield, Zoe V. Croker, Daniel Robertson, Avril A. B. Massey, Nicholas L. Donovan, Chantal Tee, Ernest Edwards, David Woodruff, Trent M. Halai, Reena Hansbro, Philip M. Cooper, Matthew A. Sci Rep Article 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 (Ca(2+)), 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 Ca(2+) 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 Ca(2+) 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 Ca(2+), 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. Nature Publishing Group UK 2018-12-13 /pmc/articles/PMC6292860/ /pubmed/30546040 http://dx.doi.org/10.1038/s41598-018-36242-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Schofield, Zoe V.
Croker, Daniel
Robertson, Avril A. B.
Massey, Nicholas L.
Donovan, Chantal
Tee, Ernest
Edwards, David
Woodruff, Trent M.
Halai, Reena
Hansbro, Philip M.
Cooper, Matthew A.
Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title_full Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title_fullStr Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title_full_unstemmed Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title_short Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
title_sort characterisation of small molecule ligands 4cmtb and 2ctap as modulators of human ffa2 receptor signalling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292860/
https://www.ncbi.nlm.nih.gov/pubmed/30546040
http://dx.doi.org/10.1038/s41598-018-36242-1
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