| Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies. | |
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MedLine Citation:
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PMID: 20496895 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Multiple N-methylation is a novel technology to improve bioavailability of peptides and increase receptor subtype selectivity. This technique has been applied here to the superpotent but nonselective cyclic peptide MT-II. A library of all possible 31 backbone N-methylated derivatives has been synthesized and tested for binding and activation at melanocortin receptor subtypes 1, 3, 4, and 5. It turned out that selectivity is improved with every introduced N-methyl group, resulting in several N-methylated selective and potent agonists for the hMC1R. The most potent of these derivatives is N-methylated on four out of five amide bonds in the cyclic structure. Its solution structure indicates a strongly preferred backbone conformation that resembles other alpha-MSH analogs but possesses much less flexibility and in addition distinct differences in the spatial arrangement of individual amino acid side chains. |
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Authors:
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Lucas Doedens; Florian Opperer; Minying Cai; Johannes G Beck; Matt Dedek; Erin Palmer; Victor J Hruby; Horst Kessler |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 132 ISSN: 1520-5126 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-10 Completed Date: 2010-09-14 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 8115-28 Citation Subset: IM |
Affiliation:
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Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amides
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chemistry* Binding, Competitive Cell Line Drug Design* Humans Methylation Molecular Dynamics Simulation Nitrogen / chemistry* Nuclear Magnetic Resonance, Biomolecular Peptides, Cyclic / chemistry*, metabolism*, pharmacology Protein Conformation Receptor, Melanocortin, Type 1 / metabolism* Receptors, G-Protein-Coupled / metabolism Substrate Specificity |
| Grant Support | |
ID/Acronym/Agency:
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DA06284/DA/NIDA NIH HHS; DK017420/DK/NIDDK NIH HHS; P01 DA006284-19/DA/NIDA NIH HHS; R01 DK017420-34/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Amides; 0/Peptides, Cyclic; 0/Receptor, Melanocortin, Type 1; 0/Receptors, G-Protein-Coupled; 7727-37-9/Nitrogen |
| Comments/Corrections | |
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