Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Pharm Res
1996 Nov 01;1311:1624-30. doi: 10.1023/a:1016424203457.
Show Gene links
Show Anatomy links
Structure-based search for peptide ligands that cross-react with melanocortin receptors.
Quillan JM
,
Sadée W
.
???displayArticle.abstract???
PURPOSE: To define sequence motifs that can be used to identify peptide ligands of the melanocortin receptor (MCR).
METHODS: Screening of combinatorial libraries has led to identification of D-Trp-Nle-NH2 (Nle, norleucine) and D-Trp-Arg-NH2 as the smallest structures known to antagonize the amphibian MCR (1). As the basis of a search paradigm, peptide-ligands containing these or similar motifs within their larger primary structure were examined for ability to antagonize amphibian and recombinant human MCRs. Compounds examined include analogs of substance P, leutinizing-hormone releasing-hormone, endothelin, neurotensin, and opioid-somatostatin.
RESULTS: Of seven compounds tested containing the predetermined search motif D-Trp-AAx (where AAx is Arg, Leu, Nle, or Ile), six were found to have previously unrecognized antagonist activity at the amphibian MCR (Kd 30 to 5000 nM). In contrast, of 14 similar control peptides lacking the D-Trp-AAx search motif, only somatostatin displayed measurable antagonist potency. The anticancer peptide, [Arg8, D-Trp7.9, N-methyl-Phe8]-substance P, was the most potent of the motif-containing peptides with a Kd of 31 nM. The mu-opioid antagonist D-Phe-cyclic[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2 (CTAP) also blocked the amphibian MCR (Kd 1 microM), but the related mu-antagonist CTOP, different only by only by substitution of Arg with ornithine within the search motif, was found to agonize the amphibian MCR (EC50 67 nM). CTAP and the anticancer peptide were also tested on human MCRs (hMCRs); while CTAP competed with alpha-MSH at the hMC1 receptor, the anticancer peptide had no effect or was slightly stimulatory.
CONCLUSIONS: We have identified dipeptide motifs that help distinguish antagonist ligands of the amphibian MCR from ligands known to interact with other G-protein coupled receptors. This approach might be generally applicable if motifs can identified for other receptors and their subtypes. In studies employing CTAP and CTOP, analogs previously considered highly selective for the mu-opioid receptor, cross-reaction with MCRs must be considered.
???displayArticle.pubmedLink???
8956325
???displayArticle.link???Pharm Res ???displayArticle.grants???[+]
Akira,
Differentiation of neural crest cells of Xenopus laevis in clonal culture.
1987, Pubmed,
Xenbase
Akira,
Differentiation of neural crest cells of Xenopus laevis in clonal culture.
1987,
Pubmed
,
Xenbase
Cannon,
Alpha melanocyte stimulating hormone inhibits immunostimulatory and inflammatory actions of interleukin 1.
1986,
Pubmed
Chen,
Molecular cloning and functional expression of a mu-opioid receptor from rat brain.
1993,
Pubmed
Clark,
Effects of opioid peptides on thermoregulation.
1981,
Pubmed
Daniolos,
Action of light on frog pigment cells in culture.
1990,
Pubmed
,
Xenbase
DeLean,
Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves.
1978,
Pubmed
Fukuzawa,
Proliferation in vitro of melanophores from Xenopus laevis.
1983,
Pubmed
,
Xenbase
Gilman,
A protein binding assay for adenosine 3':5'-cyclic monophosphate.
1970,
Pubmed
Gispen,
Interaction between ACTH fragments, brain opiate receptors and morphine-induced analgesia.
1976,
Pubmed
Halaban,
Pigmentation and proliferation of human melanocytes and the effects of melanocyte-stimulating hormone and ultraviolet B light.
1993,
Pubmed
Holdeman,
Antipyretic activity of a potent alpha-MSH analog.
1985,
Pubmed
Ide,
Proliferation of amphibian melanophores in vitro.
1974,
Pubmed
Jackson,
Differentiation of amphibian embryonic cells in vitro.
1975,
Pubmed
,
Xenbase
Jayawickreme,
Discovery and structure-function analysis of alpha-melanocyte-stimulating hormone antagonists.
1994,
Pubmed
,
Xenbase
Karne,
Cloning and characterization of an endothelin-3 specific receptor (ETC receptor) from Xenopus laevis dermal melanophores.
1993,
Pubmed
,
Xenbase
Kondo,
Long-term cultivation of amphibian melanophores. In vitro ageing and spontaneous transformation to a continuous cell line.
1983,
Pubmed
LERNER,
Effect of alpha- and betamelanocyte stimulating hormones on the skin colour of man.
1961,
Pubmed
Luger,
Production of immunosuppressing melanotropins by human keratinocytes.
1993,
Pubmed
Mountjoy,
The cloning of a family of genes that encode the melanocortin receptors.
1992,
Pubmed
Murphy,
Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone.
1983,
Pubmed
Pelton,
Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors.
1986,
Pubmed
Quillan,
Combinatorial diffusion assay used to identify topically active melanocyte-stimulating hormone receptor antagonists.
1995,
Pubmed
,
Xenbase
Sawyer,
Discovery and structure-activity relationships of novel alpha-melanocyte-stimulating hormone inhibitors.
1989,
Pubmed
Sawyer,
Alpha-melanocyte stimulating hormone message and inhibitory sequences: comparative structure-activity studies on melanocytes.
1990,
Pubmed
Strand,
Melanotropins as growth factors.
1993,
Pubmed
Terenius,
Somatostatin and ACTH are peptides with partial antagonist-like selectivity for opiate receptors.
1976,
Pubmed