title: Structure-activity studies of new melanocortin peptides containing an aromatic amino acid at the N-terminal position.
abstract: Cyclic melanotropin peptides, designed with an aromatic amino acid substitution at the N-terminal position of the MT-II-type scaffold, were prepared by solid-phase peptide synthesis and evaluated for their ability to bind to and activate human melanocortin-1, -3, -4, and -5 receptors. The structure-activity studies of these MT-II analogues have identified a selective antagonist at the hMC4R (H-Phe-c[Asp-Pro-d-Nal(2')-Arg-Trp-Gly-Lys]-NH(2), pA(2)=8.7), a selective partial agonist at the hMC4R (H-d-Nal(2')-c[Asp-Pro-d-Phe-Arg-Trp-Gly-Lys]-NH(2), IC(50)=11nM, EC(50)=56nM), and a selective partial agonist at the hMC3R (H-d-Phe-c[Asp-Pro-d-Phe-Arg-Trp-Lys]-NH(2), IC(50)=3.7nM, EC(50)=4.9nM). Aromatic amino acid substitution at the N-terminus in conjuction with the expansion of the 23-membered cyclic lactam MT-II scaffold to a 26-membered scaffold by addition of a Gly residue in position 10 leads to melanotropin peptides with enhanced receptor selectivity.
authors.affiliation: Department of Chemistry and Toxicology, University of Arizona, Tuscon, AZ 85721, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Minying
authors.initials: M
authors.lastname: Cai
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Mayorov
authors.forename: Dev
authors.initials: D
authors.lastname: Trivedi
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009074:Melanocyte-Stimulating Hormones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D044101:Receptors, Melanocortin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones