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Drug News Perspect. 2000 Feb;13(1):19-27.

MC3-R as a novel target for antiinflammatory therapy.

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1
The William Harvey Research Institute, Department of Biochemical Pharmacology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, UK.

Abstract

To date five melanocortin receptors (MC-R) have been cloned, identified and shown to have a wide distribution throughout the body and likely many diverse functions. MC1-R, found on melanocytes, is involved in pigmentation, while MC2-R is the classic adrenocorticotropic (ACTH) receptor found on the adrenal cortex and adipocytes. MC3-R, MC4-R and MC5-R are in their infancy with regard to their characterization. MC4-R has generated wide interest for its involvement in obesity, whereas our own studies have indicated a role for MC3-R in experimental inflammation. An ACTH fragment unable to alter circulating corticosterone, ACTH-4-10, acts at murine MC3-R present on peritoneal macrophage to inhibit cytokine formation and subsequent neutrophil extravasation. These findings were confirmed using agonists with a higher degree of selectivity toward MC3-R, such as gamma-2-MSH and the synthetic mixed MC3/4-R agonist MTII. In vitro, all these agents were able to affect macrophage functions, including phagocytosis and production of the CXC chemokine KC. Besides using RT-PCR and cAMP formation assays, the involvement of MC3-R in the antiinflammatory actions of these melanocortins was validated with the antagonist SHU-9119. Together these experimental data support the notion that agonism at MC3-R can be used for the design of novel therapeutics for inflammatory conditions.

PMID:
12937649
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