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Brown AJ, Tsoulou C, Ward E, et al. Pharmacological properties of acid N-thiazolylamide FFA2 agonists. Pharmacol Res Perspect. 2015;3(3):e00141doi: 10.1002/prp2.141.
Brown, A. J., Tsoulou, C., Ward, E., Gower, E., Bhudia, N., Chowdhury, F., Dean, T. W., Faucher, N., Gangar, A., & Dowell, S. J. (2015). Pharmacological properties of acid N-thiazolylamide FFA2 agonists. Pharmacology research & perspectives, 3(3), e00141. https://doi.org/10.1002/prp2.141
Brown, Andrew J, et al. "Pharmacological properties of acid N-thiazolylamide FFA2 agonists." Pharmacology research & perspectives vol. 3,3 (2015): e00141. doi: https://doi.org/10.1002/prp2.141
Brown AJ, Tsoulou C, Ward E, Gower E, Bhudia N, Chowdhury F, Dean TW, Faucher N, Gangar A, Dowell SJ. Pharmacological properties of acid N-thiazolylamide FFA2 agonists. Pharmacol Res Perspect. 2015 Jun;3(3):e00141. doi: 10.1002/prp2.141. Epub 2015 May 08. PMID: 26236484; PMCID: PMC4492757.
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Pharmacol Res Perspect. 2015 Jun;3(3):e00141. doi: 10.1002/prp2.141. Epub 2015 May 08.

Pharmacological properties of acid N-thiazolylamide FFA2 agonists.

Pharmacology research & perspectives

Andrew J Brown, Christina Tsoulou, Emma Ward, Elaine Gower, Nisha Bhudia, Forhad Chowdhury, Tony W Dean, Nicolas Faucher, Akanksha Gangar, Simon J Dowell

Affiliations

  1. Biological Sciences, GlaxoSmithKline Stevenage, United Kingdom.
  2. Respiratory Therapy Area Unit, GlaxoSmithKline Stevenage, United Kingdom.
  3. Chemical Sciences, GlaxoSmithKline Stevenage, United Kingdom.
  4. Metabolic Pathways, GlaxoSmithKline Les Ulis, France.

PMID: 26236484 PMCID: PMC4492757 DOI: 10.1002/prp2.141

Abstract

FFA2 is a receptor for short-chain fatty acids. Propionate (C3) and 4-chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide (4-CMTB), the prototypical synthetic FFA2 agonist, evoke calcium mobilization in neutrophils and inhibit lipolysis in adipocytes via this G-protein-coupled receptor. 4-CMTB contains an N-thiazolylamide motif but no acid group, and 4-CMTB and C3 bind to different sites on FFA2 and show allosteric cooperativity. Recently, FFA2 agonists have been described that contain both N-thiazolylamide and carboxylate groups, reminiscent of bitopic ligands. These are thought to engage the carboxylate-binding site on FFA2, but preliminary evidence suggests they do not bind to the same site as 4-CMTB even though both contain N-thiazolylamide. Here, we describe the characterization of four FFA2 ligands containing both N-thiazolylamide and carboxylate. (R)-3-benzyl-4-((4-(2-chlorophenyl)thiazol-2-yl)(methyl)amino)-4-oxobutanoic acid (compound 14) exhibits allosteric agonism with 4-CMTB but not C3. Three other compounds agonize FFA2 in [(35)S]GTPγS-incorporation or cAMP assays but behave as inverse agonists in yeast-based gene-reporter assays, showing orthosteric antagonism of C3 responses but allosteric antagonism of 4-CMTB responses. Thus, the bitopic-like FFA2 ligands engage the orthosteric site but do not compete at the site of 4-CMTB binding on an FFA2 receptor molecule. Compound 14 activates FFA2 on human neutrophils and mouse adipocytes, but appears not to inhibit lipolysis upon treatment of human primary adipocytes in spite of the presence of a functional FFA2 receptor in these cells. Hence, these new ligands may reveal differences in coupling of FFA2 between human and rodent adipose tissues.

Keywords: 4-CMTB; FFA2; GPR43; N-thiazolylamide; allosteric agonist; lipolysis

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