title: Systematic Backbone Conformational Constraints on a Cyclic Melanotropin Ligand Leads to Highly Selective Ligands for Multiple Melanocortin Receptors.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
authors.forename: Udaya Kiran
authors.initials: UK
authors.lastname: Marelli
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bao
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Beck
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Opperer
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rechenmacher
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Kaitlyn R
authors.initials: KR
authors.lastname: McLeod
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Morgan R
authors.initials: MR
authors.lastname: Zingsheim
authors.affiliation: Institute for Advanced Study (IAS) and Center for Integrated Protein Science (CIPSM), Department Chemie, Technische Universität München , 85747 Garching, Germany.
authors.forename: Lucas
authors.initials: L
authors.lastname: Doedens
authors.affiliation: 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.
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D009074:Melanocyte-Stimulating Hormones / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D044101:Receptors, Melanocortin / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D008024:Ligands; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones