title: Structure-function studies on the cyclic peptide MT-II, lactam derivative of alpha-melanotropin.
abstract: The alanine-substituted and the retro, enantio, and retro-enantio analogs of MT-II, a potent agonist at melanocortin (MC) receptors, were prepared by solid-phase synthesis and evaluated for their ability to bind and activate human MC3, MC4, and MC5 receptors. Replacement of His with Ala resulted in [Ala6]-MT-II with affinity and agonist potency at human MC3, MC4, and MC5 receptors similar to MT-II. Substitution of Arg with Ala gave compound 100-fold less potent than MT-II, but replacement of Phe or Trp with Ala led to inactive compounds (at the micromolar concentrations). The significant drop of potency of the retro, enantio, and retro-enantio analogs of MT-II, demonstrated a crucial role of side-chain topology, and to a lesser degree, of peptide backbone in interactions of MT-II with the melanocortin receptors. The nuclear magnetic resonance analysis of MT-II suggested involvement of Phe and Arg residues in H-bonds stabilizing the bent conformations of the peptide backbone.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. bednarek@merck.com
authors.forename: M A
authors.initials: MA
authors.lastname: Bednarek
authors.forename: M V
authors.initials: MV
authors.lastname: Silva
authors.forename: B
authors.initials: B
authors.lastname: Arison
authors.forename: T
authors.initials: T
authors.lastname: MacNeil
authors.forename: R N
authors.initials: RN
authors.lastname: Kalyani
authors.forename: R R
authors.initials: RR
authors.lastname: Huang
authors.forename: D H
authors.initials: DH
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011979:Receptors, Pituitary Hormone / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D010456:Peptides, Cyclic; D011979:Receptors, Pituitary Hormone; D000521:alpha-MSH; C029446:MSH receptor