title: Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R.
abstract: [Nle4, DPhe7]-alpha-MSH (NDP-MSH), a highly potent analogue of alpha-melanocyte-stimulating hormone (alpha-MSH), possesses nanomolar efficacies at all the melanocortin receptor subtypes except the MC2R. Evaluation of the melanocortin "message" sequence of [Nle4, DPhe7]-alpha-MSH was performed on the human melanocortin receptor subtypes designated hMC1, hMC3R, hMC4R, and hMC5R. Tetrapeptides and tripeptides were stereochemically modified to explore topochemical preferences at these receptors and to identify lead peptides possessing agonist activity and subtype selectivity. Four peptides were discovered to only bind to the hMC1 and hMC4 receptor subtypes. The tetrapeptide Ac-His-DPhe-Arg-Trp-NH2 (1) possessed 0.6 microM binding affinity at the hMC1R, 1.2 microM binding affinity at the hMC4R, and agonist activity at both receptors. The tripeptides Ac-DPhe-Arg-Trp-NH2 (6) and Ac-DPhe-Arg-DTrp-NH2 (7) possessed 2.0 and 9.1 microM binding affinities, respectively, only at the hMC4R, and both compounds effected agonist activity. The tetrapeptide Ac-His-Phe-Arg-DTrp-NH2 (4) possessed 6.3 microM affinity and full agonist activity at the hMC1R, while only binding 7% at the hMC3R, 36% at the hMC4R, and 11% at the hMC5R at a maximal concentration of 10 microM. These data demonstrate that the His-Phe-Arg-Trp message sequence of the melanocortin peptides does not bind and stimulate each melanocortin receptor in a similar fashion, as previously hypothesized. Additionally, this study identified the simplest structural agonists for the hMC1R and hMC4R receptors reported to date.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
authors.forename: C
authors.initials: C
authors.lastname: Haskell-Luevano
authors.forename: S
authors.initials: S
authors.lastname: Hendrata
authors.forename: C
authors.initials: C
authors.lastname: North
authors.forename: T K
authors.initials: TK
authors.lastname: Sawyer
authors.forename: M E
authors.initials: ME
authors.lastname: Hadley
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: C
authors.initials: C
authors.lastname: Dickinson
authors.forename: I
authors.initials: I
authors.lastname: Gantz
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D015698:Genomic Library; D006801:Humans; D007700:Kinetics; D007739:L Cells; D051379:Mice; D008969:Molecular Sequence Data; D011333:Pro-Opiomelanocortin / Q000737:chemistry; D011898:Ranidae; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists* / Q000737:chemistry / Q000502:physiology; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide / Q000819:agonists*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D016415:Sequence Alignment; D012879:Skin Physiological Phenomena; D013329:Structure-Activity Relationship; D014162:Transfection; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide; D011994:Recombinant Proteins; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; C027756:MSH, 4-Nle-7-Phe-alpha-; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP