title: Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.
abstract: The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Todorovic
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Ericson
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Palusak
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Sorensen
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wood
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Medicinal Chemistry, University of Florida , Gainesville, Florida 32610, United States.|Department of Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Haskell-Luevano
mesh_terms: D000409:Alanine / Q000378:metabolism*; D000818:Animals; D005136:Eye Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D008544:Melanocytes / Q000187:drug effects*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D044101:Receptors, Melanocortin / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D005136:Eye Proteins; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D044101:Receptors, Melanocortin; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; D009074:Melanocyte-Stimulating Hormones; D001616:beta-Galactosidase; D000409:Alanine
keywords: GPCR; Melanotropin; NDP-MSH; alanine positional scan; obesity; α-MSH