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Titolo:
BIOLOGICAL AND CONFORMATIONAL EXAMINATION OF STEREOCHEMICAL MODIFICATIONS USING THE TEMPLATE MELANOTROPIN PEPTIDE, AC-NLE-C[ASP-HIS-PHE-ARG-TRP-ALA-LYS]-NH2, ON HUMAN MELANOCORTIN RECEPTORS
Autore:
HASKELLLUEVANO C; NIKIFOROVICH G; SHARMA SD; YANG YK; DICKINSON C; HRUBY VJ; GANTZ I;
Indirizzi:
UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV ARIZONA,DEPT CHEM TUCSON AZ 85721 UNIV MICHIGAN,MED CTR,DEPT INTERNAL MED ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT PEDIAT ANN ARBOR MI 48109 UNIV MICHIGAN,MED CTR,DEPT SURG ANN ARBOR MI 48109 WASHINGTON UNIV,CTR MOL DESIGN ST LOUIS MO 63110
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 11, volume: 40, anno: 1997,
pagine: 1738 - 1748
SICI:
0022-2623(1997)40:11<1738:BACEOS>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
MELANOCYTE-STIMULATING-HORMONE; MINIMAL ACTIVE SEQUENCE; CYCLIC LACTAM ANALOGS; ALPHA-MELANOTROPIN; MOLECULAR-CLONING; AMINO-ACIDS; ENERGY PARAMETERS; PRO-OPIOCORTIN; SKIN BIOASSAY; DESIGN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
69
Recensione:
Indirizzi per estratti:
Citazione:
C. Haskellluevano et al., "BIOLOGICAL AND CONFORMATIONAL EXAMINATION OF STEREOCHEMICAL MODIFICATIONS USING THE TEMPLATE MELANOTROPIN PEPTIDE, AC-NLE-C[ASP-HIS-PHE-ARG-TRP-ALA-LYS]-NH2, ON HUMAN MELANOCORTIN RECEPTORS", Journal of medicinal chemistry, 40(11), 1997, pp. 1738-1748

Abstract

Examination of conformationally constrained melanotropin peptides le(4)-c[Asp(5)-His-Phe(7)-Arg-Trp(9)-Ala-Lys]-NH2) on four human melanotropin receptors (hMC1R, hMC3R, hMC4R, and hMC5R) resulted in identifying the importance of ligand stereochemistry at positions 5, 7, and 9 for agonist binding affinity and receptor selectivity. A trend in ligandstructure-activity relationships emerged for these peptides, with thehMC1R and hMC4R possessing similar tendencies, as did the hMC3R and hMC5R. alpha-MSH et(4)-Glu-His-Phe(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2), NDP-MSH -Tyr-Ser-Nle(4)-Glu-His-D-Phe(7)-Arg-Pro-Val-NH2), and MTII 4)-c[Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(4-10)-NH2) were also examined at each of these melanocortin receptors. Interestingly, the linear NDP-MSH possessed greater binding affinity for the hMC3R and hMC5R than did the cyclic analogue MTII. The peptide Ac-Nle-c[Asp-His-Phe-Arg-D-Trp(9)-Ala-Lys]-NH2 demonstrated the greatest differentiation in binding affinity between the hMC1R and hMC4R (78-fold). Analogue Ac-Nle-c[Asp-His-Phe(7)-Arg-Trp-Ala-Lys]-NH2 resulted in micromolar binding affinity (or greater) at the hMC3R and hMC5R, demonstrating the importance of D-Phe(7) for ligand binding potency at these receptors. Ac-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2 resulted in loss of binding affinity at the hMC5R, implicating the importance of Nle(4) (or a hydrophobic residue in this position) for binding to this receptor. Ac-Nle-c[D-Asp(5)-His-Phe-Arg-Trp-Ala-Lys]-NH2 was unable to competitively displace [I-125]NDP-MSH binding at micromolar concentrations on the hMC3R and hMC5R, suggesting the importance of chirality of Asp(5) either for ligand-receptor interactions or for orientation of the side chain lactam bridge and thestructural integrity of the peptide conformation. Energy calculationsperformed for these peptides resulted in the identification of a low-energy ligand conformer family that is common to all the ligands. The differences in ligand binding affinities observed in this study are postulated to be a result of different ligand-receptor complexed interactions and not solely to the ligand structure.

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Documento generato il 28/09/20 alle ore 15:36:28