title: Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: pharmacological and conformational studies.
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.
authors.affiliation: Institute for Advanced Study and Center for Integrated Protein Science at the Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: Lucas
authors.initials: L
authors.lastname: Doedens
authors.forename: Florian
authors.initials: F
authors.lastname: Opperer
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Beck
authors.forename: Matt
authors.initials: M
authors.lastname: Dedek
authors.forename: Erin
authors.initials: E
authors.lastname: Palmer
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000577:Amides / Q000737:chemistry*; D001667:Binding, Competitive; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008745:Methylation; D056004:Molecular Dynamics Simulation; D009584:Nitrogen / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000577:Amides; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; D043562:Receptors, G-Protein-Coupled; D009584:Nitrogen