Multiple N-methylation of MT-II Backbone Amide Bonds Leads to Melanocortin Receptor Subtype HMC1R Selectivity: Pharmacological and Conformational Studies

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2010 May 26

PMID 20496895

Citations 46

Authors

Lucas Doedens

Florian Opperer

Minying Cai

Johannes G Beck

Matt Dedek

Erin Palmer

Victor J Hruby

Horst Kessler

Affiliations

Soon will be listed here.

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.

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