TY - JOUR

T1 - Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands

AU - Hudson, Brian D

AU - Christiansen, Elisabeth

AU - Murdoch, Hannah

AU - Jenkins, Laura

AU - Hansen, Anders Højgaard

AU - Madsen, Ole

AU - Ulven, Trond

AU - Milligan, Graeme

N1 - Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

KW - Allosteric Regulation

KW - Cell Line

KW - Humans

KW - Ligands

KW - Receptors, G-Protein-Coupled

U2 - 10.1124/mol.114.093294

DO - 10.1124/mol.114.093294

M3 - Journal article

VL - 86

SP - 200

EP - 210

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -