title: Further structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5.
abstract: Recently we have demonstrated that replacing His(6) by constrained amino acids(2) in the well-known antagonist SHU-9119 resulted in potent and selective antagonist ligands especially at the hMC3R and hMC5 receptors. With the aim to further explore position 6 in the sequence of SHU-9119 and MT-II, we have designed, synthesized, and pharmacologically characterized a series of peptide analogues of MT-II and SHU-9119 at the human melanocortin receptors subtypes MC3R, MC4R and MC5R. All these peptides were modified at position 6 with constrained amino acids which are commercially available. In this study, we have identified new selective ligands for the hMC4R, and an antagonist for the hMC3/hMC4 receptors. Additionally, we have discovered an interesting new selective antagonist at the hMC3R, Ac-Nle-c[Asp-betaAla-DNal(2')-Arg-Trp-Lys]-NH(2) (2, PG-106) which represents an important tool in further biological investigations of the hMC3R. PG-106 will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Guoxia
authors.initials: G
authors.lastname: Han
authors.forename: Dev
authors.initials: D
authors.lastname: Trivedi
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D009074:Melanocyte-Stimulating Hormones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D044104:Receptor, Melanocortin, Type 3 / Q000037:antagonists & inhibitors / Q000187:drug effects; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000187:drug effects; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors / Q000187:drug effects; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007769:Lactams; D010456:Peptides, Cyclic; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C086971:melanocortin 5 receptor; C079282:melanotan-II; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones