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

- Schofield, Zoe V.; Croker, Daniel; Cooper, Matthew A.; Robertson, Avril A. B.; Massey, Nicholas L.; Donovan, Chantal; Tee, Ernest; Edwards, David; Woodruff, Trent M.; Halai, Reena; Hansbro, Philip M.

Title
Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling
Creator
Schofield, Zoe V.; Croker, Daniel; Cooper, Matthew A.; Robertson, Avril A. B.; Massey, Nicholas L.; Donovan, Chantal; Tee, Ernest; Edwards, David; Woodruff, Trent M.; Halai, Reena; Hansbro, Philip M.
Relation
Scientific Reports Vol. 8, no. 17819
Publisher Link
http://dx.doi.org/10.1038/s41598-018-36242-1
Publisher
Nature Publishing Group
Resource Type
journal article
Date
2018
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 (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.
Subject
short chain fatty acids; small molecule ligands; modulators; receptor signalling
Identifier
http://hdl.handle.net/1959.13/1409102
Identifier
uon:35944
Identifier
ISSN:2045-2322
Rights
© The Author(s) 2018. 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/.
Language
eng
Full Text
Reviewed
  • Hits: 7051
  • Visitors: 7304
  • Downloads: 292
Thumbnail File Description Size Format
ATTACHMENT02 Publisher version (open access) 1 MB Adobe Acrobat PDF
  • Disclaimer
  • Privacy
  • Copyright
  • Contact
  • Deposit