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- Title
Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.
- Authors
Montero-Melendez, Trinidad; Forfar, Rachel; Cook, Jennifer; Jerman, Jeffrey; Taylor, Debra; Perretti, Mauro
- 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 MC, MC, and MC 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, MC PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.
- Subjects
FENOPROFEN; ALLOSTERIC enzymes; MELANOCORTIN receptors; DRUG development; DRUG use testing
- Publication
Cellular & Molecular Life Sciences, 2017, Vol 74, Issue 7, p1335
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-016-2419-3