title: Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 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 MC5receptors. 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, MC3PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.
authors.affiliation: 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.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Montero-Melendez
authors.affiliation: Medical Research Council Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK.
authors.forename: Rachel A E
authors.initials: RA
authors.lastname: Forfar
authors.affiliation: Medical Research Council Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Medical Research Council Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Jerman
authors.affiliation: Medical Research Council Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Taylor
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000209:etiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D058492:Drug Repositioning; D005279:Fenoprofen / Q000494:pharmacology* / Q000627:therapeutic use; D007596:Joints / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053486:Melanocortins; D044104:Receptor, Melanocortin, Type 3; D011451:Prostaglandin-Endoperoxide Synthases; D005279:Fenoprofen
keywords: Arthritis; Drug repositioning; GPCR; Inflammation; Resolution of inflammation