2. Academic Validation
  3. Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3

  • Cell Mol Life Sci. 2017 Apr;74(7):1335-1345. doi: 10.1007/s00018-016-2419-3.
Trinidad Montero-Melendez 1,  Rachel A E Forfar 2,  Jennifer M Cook 2,  Jeffrey C Jerman 2,  Debra L Taylor 2,  Mauro Perretti 3
Affiliations

Affiliations

  • 1 The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. t.monteromelendez@qmul.ac.uk.
  • 2 Medical Research Council Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK.
  • 3 The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
PMID: 27853832 DOI: 10.1007/s00018-016-2419-3
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.

Keywords

Arthritis; Drug repositioning; GPCR; Inflammation; Resolution of inflammation.

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