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

It is well established that melanocort- ins are peptides that have potent anti-inflamma- tory 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 syn- thetic 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--in- duced activation of a NF-B transcriptional re- porter in human melanoma cells, which endog- enously 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- production in BALB/c mice. In this model, the compound had an ED50 of approxi- mately 10 mol/kg and a pharmacodynamic half- life of 8 h. Pharmacokinetic analysis of the compound indicated that the compound had a t1/2 of 1.7 h. In a model of lung inflammation, administration of 15 mol/kg BMS-470539 re- sulted in a 45% reduction in LPS-induced leu- kocyte infiltration (an infiltrate comprised pri- marily of neutrophils). The compound was also effective in a model of delayed-type hypersensi- tivity, reducing paw swelling by 59%, compara- ble 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. J. Leukoc. Biol. 80: 897-904; 2006.