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 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.
Kang
Liya
L
Bristol-Myers Squibb Pharmaceutical Research Institute, Pennington, NJ 08534, USA.
McIntyre
Kim W
KW
Gillooly
Kathleen M
KM
Yang
Yifan
Y
Haycock
John
J
Roberts
Stephen
S
Khanna
Ashish
A
Herpin
Timothy F
TF
Yu
Guixue
G
Wu
Ximao
X
Morton
George C
GC
Tuerdi
Huji
H
Koplowitz
Barry
B
Walker
Stephen G
SG
Wardwell-Swanson
Judy
J
Macor
John E
JE
Lawrence
R Michael
RM
Carlson
Kenneth E
KE
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry; D007249:Inflammation / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists*; D013329:Structure-Activity Relationship; D013997:Time Factors
C523069:BMS-470539; D016207:Cytokines; D007093:Imidazoles; D008070:Lipopolysaccharides; D044102:Receptor, Melanocortin, Type 1