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

Lucas Doedens, Florian Opperer, Minying Cai, Johannes G. Beck, Matt Dedek, Erin Palmer, Victor J Hruby, Horst Kessler

Research output: Contribution to journalArticle

71 Scopus citations

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 α-MSH analogs but possesses much less flexibility and in addition distinct differences in the spatial arrangement of individual amino acid side chains.

Original languageEnglish (US)
Pages (from-to)8115-8128
Number of pages14
JournalJournal of the American Chemical Society
Volume132
Issue number23
DOIs
Publication statusPublished - Jun 16 2010

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ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

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