Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3 |
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Authors: | Trinidad Montero-Melendez Rachel A E Forfar Jennifer M Cook Jeffrey C Jerman Debra L Taylor Mauro Perretti |
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Institution: | 1.The William Harvey Research Institute, Barts and The London School of Medicine,Queen Mary University of London,London,UK;2.Medical Research Council Technology,Centre for Therapeutics Discovery,London,UK |
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Abstract: | The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases. |
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