title: Potent and selective MC-4 receptor agonists based on a novel disulfide scaffold.
abstract: Extensive structure-activity relationship studies utilizing a beta-MSH-derived cyclic nonapeptide, Ac-Tyr-Arg-[Cys-Glu-His-D-Phe-Arg-Trp-Cys]-NH(2) (3), led to identification of a series of novel MC-4R selective disulfide-constrained hexapeptide analogs including Ac-[hCys-His-D-Phe-Arg-Trp-Cys]-NH(2) (12). The structural modifications associated with profound influence on MC-4R potency and selectivity were ring size, ring conformation, and the aromatic substitution of the D-Phe7. These cyclic peptide analogs provide novel and enhanced reagents for use in the elucidation of melanocortin-4 receptor-related physiology, and may additionally find application in the treatment of obesity and related metabolic disorders.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN 46285, USA. lyan@lilly.com
authors.forename: Liang Z
authors.initials: LZ
authors.lastname: Yan
authors.forename: David
authors.initials: D
authors.lastname: Flora
authors.forename: Patrick
authors.initials: P
authors.lastname: Edwards
authors.forename: David L
authors.initials: DL
authors.lastname: Smiley
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Emmerson
authors.forename: Hansen M
authors.initials: HM
authors.lastname: Hsiung
authors.forename: Robert
authors.initials: R
authors.lastname: Gadski
authors.forename: JeAnne
authors.initials: J
authors.lastname: Hertel
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heiman
authors.forename: Saba
authors.initials: S
authors.lastname: Husain
authors.forename: Thomas P
authors.initials: TP
authors.lastname: O'Brien
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dimarchi
authors.forename: John P
authors.initials: JP
authors.lastname: Mayer
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004220:Disulfides / Q000737:chemistry*; D013058:Mass Spectrometry; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004220:Disulfides; D044105:Receptor, Melanocortin, Type 4