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

Autor:	Nicholas L. Massey, Reena Halai, Mark E. Cooper, Philip M. Hansbro, Zoe Schofield, Chantal Donovan, Avril A. B. Robertson, Daniel E. Croker, Ernest H. L. Tee, David Edwards, Trent M. Woodruff
Jazyk:	angličtina
Rok vydání:	2018
Předmět:	0301 basic medicine MAP Kinase Signaling System Allosteric regulation lcsh:Medicine Receptors Cell Surface CHO Cells Ligands Second Messenger Systems Article 03 medical and health sciences chemistry.chemical_compound Mice Cricetulus Free fatty acid receptor 2 Extracellular Cyclic AMP Animals Humans Cyclic adenosine monophosphate Receptor lcsh:Science Mitogen-Activated Protein Kinase 1 Multidisciplinary Mitogen-Activated Protein Kinase 3 Kinase lcsh:R Fatty Acids Volatile Small molecule 030104 developmental biology chemistry Biochemistry Phosphorylation lcsh:Q
Zdroj:	Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-018-36242-1
Popis:	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.
Databáze:	OpenAIRE
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