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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Abstract
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 |
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| Status: | Published |
| Refereed: | Yes |
| 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: | 0026-895X |
| 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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