title: Design of a new peptidomimetic agonist for the melanocortin receptors based on the solution structure of the peptide ligand, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2).
abstract: The solution structure of a potent melanocortin receptor agonist, Ac-Nle-cyclo[Asp-Pro-DPhe-Arg-Trp-Lys]-NH(2) (1) was calculated using distance restraints determined from 1H NMR spectroscopy. Eight of the lowest energy conformations from this study were used to identify non-peptide cores that mimic the spatial arrangement of the critical tripeptide region, DPhe-Arg-Trp, found in 1. From these studies, compound 2a, containing the cis-cyclohexyl core, was identified as a functional agonist of the melanocortin-4 receptor (MC4R) with an IC(50) and EC(50) below 10 nM. Compound 2a also showed 36- and 7-fold selectivity over MC3R and MC1R, respectively, in the binding assays. Subtle changes in cyclohexane stereochemistry and removal of functional groups led to analogues with lower affinity for the MC receptors.
authors.affiliation: Departments of Small Molecule Drug Discovery and Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, 91320, CA, USA. cfotsch@amgen.com
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Smith
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Adams
authors.forename: Janet
authors.initials: J
authors.lastname: Cheetham
authors.forename: Michael
authors.initials: M
authors.lastname: Croghan
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jarosinski
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Nuria A
authors.initials: NA
authors.lastname: Tamayo
authors.forename: Ning
authors.initials: N
authors.lastname: Xi
authors.forename: James W
authors.initials: JW
authors.lastname: Baumgartner
mesh_terms: D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D044101:Receptors, Melanocortin / Q000819:agonists*; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D010455:Peptides; D010456:Peptides, Cyclic; D044101:Receptors, Melanocortin; D011994:Recombinant Proteins; C481396:acetyl-norleucyl-cyclo(aspartyl-prolyl-D-phenylalanyl-arginyl-tryptophyl-lysyl )amide