Discovery and in vivo evaluation of new melanocortin-4 receptor-selective peptides
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. - \ 2003
Peptides 24 (2003)2. - ISSN 0196-9781 - p. 271 - 280.
melanocyte-stimulating hormone - alpha-melanotropin action - agouti-related protein - evaluation in-vitro - biological evaluation - molecular-cloning - inverse agonist - msh analogs - amino-acid - rat
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.
Increased rigidity with age in social behavior of Java-monkeys (Macaca fascicularis)
Veenema, H.C. ; Hooff, J.A.R.A.M. van; Gispen, W.H. ; Spruijt, B.M. - \ 2001
Neurobiology of aging 22 (2001)2. - ISSN 0197-4580 - p. 273 - 281.
In this study we investigated the effect of aging on the structure of behavior of socially housed Java-monkeys. Indices of the sequential structure of an animal's own ongoing behavior and of its responses to behavior of other animals were calculated using an information statistic approach. These indices reflect information-processing abilities of an animal, as they represent the ability of an animal to adjust its behavior in response to actions by interaction partners. The influence of an animal's dominance history on the age-related changes was investigated as well. In the literature social subordinance in monkeys is generally associated with elevated levels of cortisol which, in turn, have been suggested to influence information processing abilities. In this study, old animals of low dominance history became more rigid in their own ongoing behavior, whereas old animals of high dominance history did not differ from young animals. The ability of old animals to maintain normal levels of predictability during social interactions declined, but only in social interactions with unfamiliar animals, such as young or unrelated animals. These results may explain the generally found social withdrawal of old non-human primates.
|Synthesis of cyclic alpha-MSH peptides
Schaaper, W.M.M. ; Adan, R.A.H. ; Posthuma, T.A. ; Oosterom, J. ; Gispen, W.H. ; Meloen, R.H. - \ 1998
Letters in peptide science 5 (1998)2-3. - ISSN 0929-5666 - p. 205 - 208.
Cyclic lactam analogs of α-melanocyte stimulating hormone (α-MSH) have been shown to be potent agonists in the frog skin bioassay [Al-Obeidi, F. et al., J. Med. Chem., 32 (1989) 2555], demonstrating melanocortin-1 (MC1) receptor activity. We synthesized cyclic α-MSH(1-13) and α-MSH(4-10) lactam analogs. The peptides were synthesized using Fmoc chemistry. We improved the cyclization procedure: side chains of Asp5 and Lys10 from the deprotected peptide were coupled in DMF to form a cyclic lactam, using an excess of PyBOP reagent and DIEA as a base. The cyclization reaction was completed within 1 h and was almost quantitative. We also synthesized an α-MSH analog cyclized via a disulphide bridge. The peptides were tested for their selectivity for the rat MC4 receptor. Cyclization and substitutions at position 7 dramatically influenced the selectivity for the rMC4 receptor.
|Neurite outgrowth in Neuro 2A cells is stimulated by activation of melanocortin receptors.
Adan, R.A.H. ; Kraan, M. van de; Oosterom, J. ; Wiegant, V.M. ; Burbach, J.P.H. ; Gispen, W.H. - \ 1995
In: Proc. 25th Annual Meeting Society for Neuroscience. San Diego (1995) 228.7
|Differential effects of melanocortin peptides on neural melanocortin receptors.
Adan, R.A.H. ; Oosterom, J. ; Wiegant, V.M. ; Burbach, J.P.H. ; Gispen, W.H. - \ 1995
In: Proc. 24th Annual meeting Society for Neuroscience. Miami Beach (1995) 220.4