Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 366055
Title Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides
Author(s) Nijenhuis, W.A.J.; Kruijtzer, J.A.W.; Wanders, N.; Vrinten, D.H.; Garner, K.M.; Schaaper, W.M.M.; Meloen, R.H.; Gispen, W.H.; Liskamp, R.M.; Adan, R.A.H.
Source Peptides 24 (2003)2. - ISSN 0196-9781 - p. 271 - 280.
DOI https://doi.org/10.1016/S0196-9781(03)00032-9
Department(s) Central Institute for Animal Disease Control
Publication type Refereed Article in a scientific journal
Publication year 2003
Keyword(s) melanocyte-stimulating hormone - alpha-melanotropin action - agouti-related protein - evaluation in-vitro - biological evaluation - molecular-cloning - inverse agonist - msh analogs - amino-acid - rat
Abstract The melanocortin-4 receptor (MC4R) is involved in several physiological processes, including body weight regulation and grooming behaviour in rats. It has also been suggested that the MC4R mediates the effects of melanocortin ligands on neuropathic pain. Selective compounds are needed to study the exact role of the MC4R in these different processes. We describe here the development and evaluation of new melanocortin compounds that are selective for the MC4R as compared with the other centrally expressed receptors, MC3R and MC5R. First, a library of 18 peptides, in which a melanocortin-based sequence was systematically point-mutated, was screened for binding to and activity on the MC3R, MC4R and MC5R. Compound Ac-Nle-Gly-Lys-Image-Phe-Arg-Trp-Gly-NH2 (JK1) appeared to be the most selective MC4R compound, based on affinity. This compound is 90- and 110-fold selective for the MC4R as compared to the MC3R and MC5R, respectively. Subsequent modification of JK1 yielded compound Ac-Nle-Gly-Lys-Image-Nal(2)-Arg-Trp-Gly-NH2 (JK7), a selective MC4R antagonist with 34-fold MC4R/MC3R and 109-fold MC4R/MC5R selectivity. The compounds were active in vivo as determined in a grooming assay and a model for neuropathic pain in rats. Intravenous (i.v.) injections suggested that they were able to pass the blood¿brain barrier. The compounds identified here will be useful in further research on the physiological roles of the MC4R.
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