Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

Int J Mol Sci. 2021 Feb 10;22(4):1763. doi: 10.3390/ijms22041763.


The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

Keywords: FFAR; Free fatty acid receptor; GPCR; allosteric modulator; drug discovery.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation / drug effects*
  • Animals
  • Drug Discovery* / methods
  • Humans
  • Ligands
  • Models, Molecular
  • Receptors, Cell Surface / agonists
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • FFA2R protein, human
  • FFAR1 protein, human
  • FFAR3 protein, human
  • FFAR4 protein, human
  • Ligands
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries