A selective small molecule agonist of the melanocortin-1 receptor inhibits lipopolysaccharide-induced cytokine accumulation and leukocyte infiltration in mice

J Leukoc Biol. 2006 Oct;80(4):897-904. doi: 10.1189/jlb.1204748. Epub 2006 Aug 3.


It is well established that melanocortins are peptides that have potent anti-inflammatory activity. Recent research has focused on understanding which of the known melanocortin receptors mediates the anti-inflammatory actions of the melanocortins. The aim of this study was to assess the anti-inflammatory activity of a synthetic MC-1R agonist. BMS-470539 is a potent, selective, full agonist of human and murine MC-1R with EC(50) values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS-470539 dose-dependently inhibited TNF-alpha-induced activation of a NF-kappaB transcriptional reporter in human melanoma cells, which endogenously express MC-1R. In vivo studies with BMS-470539 demonstrated that subcutaneous administration of BMS-470539 resulted in a dose-dependent inhibition of LPS-induced TNF-alpha production in BALB/c mice. In this model, the compound had an ED(50) of approximately 10 micromol/kg and a pharmacodynamic half-life of approximately 8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t(1/2) of 1.7 h. In a model of lung inflammation, administration of 15 micromol/kg BMS-470539 resulted in a 45% reduction in LPS-induced leukocyte infiltration (an infiltrate comprised primarily of neutrophils). The compound was also effective in a model of delayed-type hypersensitivity, reducing paw swelling by 59%, comparable with that seen with 5 mg/kg dexamethasone. These studies demonstrate that a selective small molecule agonist of the melanocortin-1 receptor is a potent anti-inflammatory agent in vivo and provides compelling evidence for the involvement of this receptor in the modulation of inflammation.

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Cytokines / biosynthesis
  • Cytokines / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / chemistry
  • Inflammation / immunology
  • Leukocytes / drug effects*
  • Leukocytes / immunology
  • Lipopolysaccharides / antagonists & inhibitors*
  • Lipopolysaccharides / pharmacology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Weight
  • Receptor, Melanocortin, Type 1 / agonists*
  • Structure-Activity Relationship
  • Time Factors


  • BMS-470539
  • Cytokines
  • Imidazoles
  • Lipopolysaccharides
  • Receptor, Melanocortin, Type 1