title: Analogs of lactam derivatives of alpha-melanotropin with basic and acidic residues.
abstract: A role of the aromatic and of the basic residues of the potent agonist (MTII) and antagonist (SHU9119) at the human melanocortin receptors 4 in the formation and stabilization of ligand-receptor complexes was examined. Analogs of MTII and SHU9119 with glutamic acid replacing one amino acid at a time were synthesized and tested for their ability to bind to and activate human melanocortin receptors 3, 4, and 5. Replacement of Phe (Nal) or Trp with Glu resulted in analogs of MTII and SHU9119 which were practically inactive at the receptors studied. The rather large (and unexpected) tolerance toward the presence of Glu in the position of His or Arg of MTII and SHU9119 clearly suggested that in the ligand receptor complexes these basic residues are not in contact with the receptors but probably face the extracellular environment. This identified the aromatic residues of MTII and SHU9119 as the primary structural features determining interactions of the agonist/antagonist with hMCR3-5.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. maria_bednarek@merck.com
authors.forename: M A
authors.initials: MA
authors.lastname: Bednarek
authors.forename: T
authors.initials: T
authors.lastname: MacNeil
authors.forename: R N
authors.initials: RN
authors.lastname: Kalyani
authors.forename: R
authors.initials: R
authors.lastname: Tang
authors.forename: L H
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: D H
authors.initials: DH
authors.lastname: Weinberg
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009074:Melanocyte-Stimulating Hormones / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000378:metabolism; D044101:Receptors, Melanocortin; D011994:Recombinant Proteins / Q000378:metabolism; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D011994:Recombinant Proteins; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; C086971:melanocortin 5 receptor; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones