The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism

Mol Pharmacol. 2013 Nov;84(5):710-25. doi: 10.1124/mol.113.087783. Epub 2013 Aug 26.

Abstract

TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca²⁺ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca²⁺ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Arrestins / physiology
  • Biphenyl Compounds / pharmacology*
  • Calcium / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / physiology
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Phenylpropionates / pharmacology*
  • Phosphorylation
  • Receptors, G-Protein-Coupled / agonists*
  • beta-Arrestin 1
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • 3-(4-((4-fluoro-4'-methyl-(1,1'-biphenyl)-2-yl)methoxy)phenyl)propanoic acid
  • ARRB1 protein, human
  • ARRB2 protein, human
  • Arrb1 protein, mouse
  • Arrb2 protein, mouse
  • Arrestins
  • Biphenyl Compounds
  • FFAR4 protein, human
  • Phenylpropionates
  • Receptors, G-Protein-Coupled
  • beta-Arrestin 1
  • beta-Arrestin 2
  • beta-Arrestins
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Glucose
  • Calcium