PMID: 8956325Nov 1, 1996Paper

Structure-based search for peptide ligands that cross-react with melanocortin receptors

Pharmaceutical Research
J M Quillan, W Sadée

Abstract

To define sequence motifs that can be used to identify peptide ligands of the melanocortin receptor (MCR). 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. 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 ...Continue Reading

Citations

Jan 18, 2018·ChemMedChem·Albert J KooistraChris de Graaf
Oct 17, 2006·Basic & Clinical Pharmacology & Toxicology·Helgi B SchiöthJarl E S Wikberg
Mar 23, 2006·Pharmaceutical Research·Julie L LucasWolfgang Sadée

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