Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

2012 ◽  
Vol 55 (8) ◽  
pp. 3960-3974 ◽  
Author(s):  
Nobuyuki Negoro ◽  
Shinobu Sasaki ◽  
Satoshi Mikami ◽  
Masahiro Ito ◽  
Yoshiyuki Tsujihata ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
G Protein Coupled ◽  
Acetic Acids ◽  
Fatty Acid Receptor

scholarly journals Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein–Coupled Receptor 120

2016 ◽  
Vol 89 (5) ◽  
pp. 505-520 ◽  
Author(s):  
Rudi Prihandoko ◽  
Elisa Alvarez-Curto ◽  
Brian D. Hudson ◽  
Adrian J. Butcher ◽  
Trond Ulven ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
G Protein ◽  
G Protein Coupled Receptor ◽  
Acid Receptor ◽  
Free Fatty Acid Receptor ◽  
G Protein Coupled ◽  
Fatty Acid Receptor

scholarly journals Selective Orthosteric Free Fatty Acid Receptor 2 (FFA2) Agonists

2011 ◽  
Vol 286 (12) ◽  
pp. 10628-10640 ◽  
Author(s):  
Johannes Schmidt ◽  
Nicola J. Smith ◽  
Elisabeth Christiansen ◽  
Irina G. Tikhonova ◽  
Manuel Grundmann ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
G Protein ◽  
Carboxylic Acids ◽  
Rational Design ◽  
Acid Receptor ◽  
Relationship Analysis ◽  
Arginine Residues ◽  
Free Fatty Acid Receptor ◽  
Fatty Acid Receptor

Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane receptor for short-chain fatty acids (SCFAs) that is implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency for FFA2 and can hence be considered as highly potent given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2-selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids was examined using holistic, label-free dynamic mass redistribution technology for primary screening and the receptor-proximal G protein [35S]guanosine 5′-(3-O-thio)triphosphate activation, inositol phosphate, and cAMP accumulation assays for hit confirmation. Structure-activity relationship analysis allowed formulation of a general rule to predict selectivity for small carboxylic acids at the orthosteric binding site where ligands with substituted sp3-hybridized α-carbons preferentially activate FFA3, whereas ligands with sp2- or sp-hybridized α-carbons prefer FFA2. The orthosteric binding mode was verified by site-directed mutagenesis: replacement of orthosteric site arginine residues by alanine in FFA2 prevented ligand binding, and molecular modeling predicted the detailed mode of binding. Based on this, selective mutation of three residues to their non-conserved counterparts in FFA3 was sufficient to transfer FFA3 selectivity to FFA2. Thus, selective activation of FFA2 via the orthosteric site is achievable with rather small ligands, a finding with significant implications for the rational design of therapeutic compounds selectively targeting the SCFA receptors.

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