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The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology. (Proteochemometric group)
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2006 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, no 6, 1443-1450 p.Article in journal (Refereed) Published
Abstract [en]

Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH, alpha-MSH, MS05, Ac-MS06 and Ac-[Ser12]MS06 caused dose dependent inhibition of the lipopolysaccharide (LPS)-induced increase of NO overproduction in the mice forebrain whereas MSH core modified peptides Ac-[Asp9,Ser12]MS06, [Asp9]alpha-MSH and [Asp16]beta-MSH were devoid of this effect in doses up to 10 nmol per mouse. When the minimal effective dose required for inhibition of NO production was correlated with the in vitro binding activity to MC receptor subtypes a strong and significant correlation was found for the MC3 receptor (r = 0.90; p = 0.0008), whereas weak correlation was present for the other receptors. Our results suggest that the MC3 receptor is the major player in mediating the anti-inflammatory activity of MCs in the central nervous system.

Place, publisher, year, edition, pages
2006. Vol. 27, no 6, 1443-1450 p.
Keyword [en]
Animals, Anti-Inflammatory Agents/pharmacology, Central Nervous System/pathology, Electron Spin Resonance Spectroscopy, Inflammation/*pathology, Insects, Lipopolysaccharides/metabolism, Male, Mice, Mice; Inbred ICR, Nitric Oxide/*antagonists & inhibitors/*chemistry, Peptides/chemistry, Protein Binding, Receptor; Melanocortin; Type 3/*chemistry, Receptors; Melanocortin/metabolism
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-104272DOI: 10.1016/j.peptides.2005.12.002PubMedID: 16414147OAI: oai:DiVA.org:uu-104272DiVA: diva2:219585
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2010-05-27Bibliographically approved

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