Christiansen, E., Hudson, B. D. , Hansen, A. H., Milligan, G. and Ulven, T. (2016) Development and characterization of a potent free fatty acid receptor 1 (FFA1) fluorescent tracer. Journal of Medicinal Chemistry, 59(10), pp. 4849-4858. (doi: 10.1021/acs.jmedchem.6b00202) (PMID:27074625)
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Abstract
The free fatty acid receptor 1 (FFA1/GPR40) is a potential target for treatment of type 2 diabetes. Although several potent agonists have been described, there remains a strong need for suitable tracers to interrogate ligand binding to this receptor. We address this by exploring fluorophore-tethering to known potent FFA1 agonists. This led to the development of 4, a high affinity FFA1 tracer with favorable and polarity-dependent fluorescent properties. A close to ideal overlap between the emission spectrum of the NanoLuciferase receptor tag and the excitation spectrum of 4 enabled the establishment of a homogenous BRET-based binding assay suitable for both detailed kinetic studies and high throughput competition binding studies. Using 4 as a tracer demonstrated that the compound acts fully competitively with selected synthetic agonists but not with lauric acid and allowed for the characterization of binding affinities of a diverse selection of known FFA1 agonists, indicating that 4 will be a valuable tool for future studies at FFA1.
| Item Type: | Articles |
|---|---|
| Additional Information: | The study has been funded by the Danish Council for Independent Research | Technology and Production Sciences (grant 09-070364), the Danish Council for Strategic Research (grant 11-116196) and the University of Southern Denmark. EC is supported by a fellowship from the Lundbeck Foundation. BDH is supported by a fellowship from the University of Glasgow. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Hudson, Dr Brian and Milligan, Professor Graeme |
| Authors: | Christiansen, E., Hudson, B. D., Hansen, A. H., Milligan, G., and Ulven, T. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Journal of Medicinal Chemistry |
| Publisher: | American Chemical Society |
| ISSN: | 0022-2623 |
| ISSN (Online): | 1520-4804 |
| Published Online: | 13 April 2016 |
| Copyright Holders: | Copyright © 2016 American Chemical Society |
| First Published: | First published in Journal of Medicinal Chemistry 59(10):4849-4858 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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