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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 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.

SUBMITTER: Montero-Melendez T

PROVIDER: S-EPMC5346439 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Montero-Melendez Trinidad T Forfar Rachel A E RA Cook Jennifer M JM Jerman Jeffrey C JC Taylor Debra L DL Perretti Mauro M

Cellular and molecular life sciences : CMLS 20161116 7

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< ...[more]

PMID: 27853832

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

Publications

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

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