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Published online before print August 3, 2006

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(Journal of Leukocyte Biology. 2006;80:897-904.)
© 2006 by Society for Leukocyte Biology

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

Liya Kang, Kim W. McIntyre^*, Kathleen M. Gillooly^*, Yifan Yang, John Haycock, Stephen Roberts, Ashish Khanna, Timothy F. Herpin^*, Guixue Yu, Ximao Wu, George C. Morton, Huji Tuerdi, Barry Koplowitz, Stephen G. Walker, Judy Wardwell-Swanson, John E. Macor, R. Michael Lawrence and Kenneth E. Carlson^,1

Bristol-Myers Squibb Pharmaceutical Research Institute,
^* Princeton and
Pennington, New Jersey, and
Wallingford, Connecticut; and
Department of Engineering Materials, University of Sheffield, Sheffield, United Kingdom

¹ Correspondence: Bristol-Myers Squibb Pharmaceutical Research Institute, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534. E-mail: kenneth.carlson{at}bms.com

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 EC₅₀ values in a cAMP accumulation assay of 16.8 and 11.6 nM, respectively. BMS-470539 dose-dependently inhibited TNF--induced activation of a NF-B 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- production in BALB/c mice. In this model, the compound had an ED₅₀ of approximately 10 µmol/kg and a pharmacodynamic half-life of 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 µmol/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.

Key Words: inflammation • MC-1R • NF-B • GPCR • -melanocyte-stimulating hormone

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