title: Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands.
abstract: Analysis of the roles of the short chain fatty acid receptor, free fatty acid 3 receptor (FFA3), has been severely limited by the low potency of its endogenous ligands, the crossover of function of these on the closely related free fatty acid 2 receptor, and a dearth of FFA3-selective synthetic ligands. From a series of hexahydroquinolone-3-carboxamides, we demonstrate that 4-(furan-2-yl)-2-methyl-5-oxo-N-(o-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide is a selective and moderately potent positive allosteric modular (PAM)-agonist of the FFA3 receptor. Modest chemical variations within this series resulted in compounds completely lacking activity, acting as FFA3 PAMs, or appearing to act as FFA3-negative allosteric modulators. However, the pharmacology of this series was further complicated in that certain analogs displaying overall antagonism of FFA3 function actually appeared to generate their effects via a combined positive allosteric binding cooperativity and negative allosteric effect on orthosteric ligand maximal signaling response. These studies show that various PAM-agonist and allosteric modulators of FFA3 can be identified and characterized. However, within the current chemical series, considerable care must be taken to define the pharmacological characteristics of specific compounds before useful predictions of their activity and their use in defining specific roles of FFA3 in either in vitro and in vivo settings can be made.
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hudson
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christiansen
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Hannah
authors.initials: H
authors.lastname: Murdoch
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Laura
authors.initials: L
authors.lastname: Jenkins
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Anders Højgaard
authors.initials: AH
authors.lastname: Hansen
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Ole
authors.initials: O
authors.lastname: Madsen
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.).
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (B.D.H., H.M., L.J., G.M.); and Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Odense M, Denmark (E.C., A.H.H., O.M., T.U.) Graeme.Milligan@glasgow.ac.uk.
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C106262:FFAR3 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled