Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4

Watterson, K. R. et al. (2017) Probe-dependent negative allosteric modulators of the long-chain free fatty acid receptor FFA4. Molecular Pharmacology, 91(6), pp. 630-641. (doi: 10.1124/mol.116.107821) (PMID:28385906) (PMCID:PMC5438128)

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High-affinity and selective antagonists that are able to block the actions of both endogenous and synthetic agonists of G protein–coupled receptors are integral to analysis of receptor function and to support suggestions of therapeutic potential. Although there is great interest in the potential of free fatty acid receptor 4 (FFA4) as a novel therapeutic target for the treatment of type II diabetes, the broad distribution pattern of this receptor suggests it may play a range of roles beyond glucose homeostasis in different cells and tissues. To date, a single molecule, 4-methyl-N-9H-xanthen-9-yl-benzenesulfonamide (AH-7614), has been described as an FFA4 antagonist; however, its mechanism of antagonism remains unknown. We synthesized AH-7614 and a chemical derivative and demonstrated these to be negative allosteric modulators (NAMs) of FFA4. Although these NAMs did inhibit FFA4 signaling induced by a range of endogenous and synthetic agonists, clear agonist probe dependence in the nature of allosteric modulation was apparent. Although AH-7614 did not antagonize the second long-chain free fatty acid receptor, free fatty acid receptor 1, the simple chemical structure of AH-7614 containing features found in many anticancer drugs suggests that a novel close chemical analog of AH-7614 devoid of FFA4 activity, 4-methyl-N-(9H-xanthen-9-yl)benzamide (TUG-1387), will also provide a useful control compound for future studies assessing FFA4 function. Using TUG-1387 alongside AH-7614, we show that endogenous activation of FFA4 expressed by murine C3H10T1/2 mesenchymal stem cells is required for induced differentiation of these cells toward a more mature, adipocyte-like phenotype.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Alvarez-Curto, Dr Elisa and Watterson, Dr Kenneth and Yarwood, Dr Stephen and Hudson, Dr Brian and Dunlop, Mrs Julia and Milligan, Professor Graeme
Authors: Watterson, K. R., Hansen, S. V.F., Hudson, B., Alvarez-Curto, E., Raihan, S. Z., Azevedo, C. M.G., Martin, G., Dunlop, J., Yarwood, S. J., Ulven, T., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Molecular Pharmacology
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN (Online):1521-0111
Published Online:06 April 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Molecular Pharmacology 91(6):630-641
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618921GPR120: a G protein-coupled receptor with the potential to regulate insulin secretion and inflammationGraeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/K019864/1RI MOLECULAR CELL & SYSTEMS BIOLOGY