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J Med Chem. 2015 Aug 27;58(16):6359-67. doi: 10.1021/acs.jmedchem.5b00102. Epub 2015 Aug 11.

Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors.

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Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
Department of Chemistry, Faculty of Science, King Abdulaziz University , 21589 Jeddah, Saudi Arabia.


Human melanocortin receptors (hMCRs) have been challenging targets to develop ligands that are explicitly selective for each of their subtypes. To modulate the conformational preferences of the melanocortin ligands and improve the biofunctional agonist/antagonist activities and selectivities, we have applied a backbone N-methylation approach on Ac-Nle-c[Asp-His-D-Nal(2')-Arg-Trp-Lys]-NH2 (Ac-Nle(4)-c[Asp(5),D-Nal(2')(7),Lys(10)]-NH2), a nonselective cyclic peptide antagonist at hMC3R and hMC4R and an agonist at hMC1R and hMC5R. Systematic N-methylated derivatives of Ac-Nle(4)-c[Asp(5),D-Nal(2')(7),Lys(10)]-NH2, with all possible backbone N-methylation combinations, have been synthesized and examined for their binding and functional activities toward melanocortin receptor subtypes 1, 3, 4, and 5 (hMCRs). Several N-methylated analogues are selective and potent agonists or antagonists for hMC1R or hMC5R or have selective antagonist activity for hMC3R. The selective hMC1R ligands show strong binding for human melanoma cells. We have also discovered the first universal antagonist (compound 19) for all subtypes of hMCRs.

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