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J Am Chem Soc. 2010 Jun 16;132(23):8115-28. doi: 10.1021/ja101428m.

Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies.

Author information

1
Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.

Abstract

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.

PMID:
20496895
PMCID:
PMC2895553
DOI:
10.1021/ja101428m
[Indexed for MEDLINE]
Free PMC Article

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