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

Abstract

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.

Influence of Dexamethasone on Protease-Activated Receptor 2-Mediated Responses in the Airways

“…Additional studies were conducted to determine whether f-LIGRL-NH 2 -induced inhibition of neutrophil infiltration was modulated by cotreatment with the glucocorticoid dexamethasone. In these studies, pretreatment of lipopolysaccharide-exposed mice with dexamethasone alone was associated with reduced BAL neutrophil numbers, as previously demonstrated by others (Lefort et al, 2001;Birrell et al, 2004;Kang et al, 2006;Moschos et al, 2007). Of particular interest, the inhibitory effect of f-LIGRL-NH 2 on neutrophil infiltration in lipopolysaccharide-exposed mice was significantly greater in mice that were cotreated with dexamethasone.…”

Deficiency in Melanocortin 1 Receptor Signaling Predisposes to Vascular Endothelial Dysfunction and Increased Arterial Stiffness in Mice and Humans

“…Although there has been controversies over the importance of MC1-R in modulating inflammatory responses in the skin, 20,21 several studies have shown that selective activation of the MC1-R by pharmacological means suppresses inflammatory responses in other disease models, such as vasculitis and lung inflammation. 22,23 However, to the best of our knowledge, no study has ever demonstrated that deficient MC1-R function is inherently associated with inflammation. Accordingly, the data on the inflammatory profile of MC1R e/e mice provide novel insights into the role of MC1-R as a physiological regulator of inflammatory responses.…”

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

“…8,9 Conversely, selective MC1-R and MC3-R agonists exert anti-inflammatory actions and put in motion proresolving processes. [10][11][12][13] Recent data also indicate that MC1-R activation in an inflamed vasculature can inhibit cell adhesion and migration by acting on the adherent leukocytes and reduce the levels of a variety of chemokines, which are known to contribute to the pathogenesis of atherosclerosis. However, these findings have been exclusively derived from acute experiments such as vascular and cardiac ischemia/reperfusion models, whereas the potential of MC1-R and MC3-R activation in chronic inflammatory conditions such as atherosclerosis remains unexplored.…”