Selective properties of C- and N-terminals and core residues of the melanocyte-stimulating hormone on binding to the human melanocortin receptor subtypes.
We synthesised nine analogues of [Nle4,D-Phe7]alpha-MSH (melanocyte-stimulating hormone) (NDP) where (1) the N- or C-terminals were deleted or exchanged by those of beta- or gamma-MSH and (2) the core residues His6, Phe7, Arg8 and Trp9 were individually substituted by Glu6, beta-(2-naphthyl)-D-alanine (D-Nal7), Lys8 and His9, respectively. We tested these analogues in ligand binding assays with cells transiently expressing the human melanocortin MC1, MC3, MC4 and MC5 receptors. The results show that the N-terminal segment (Ser1-Tyr2-Ser3) of NDP was not important for binding to melanocortin MC1 and MC4 receptors whereas it affects binding to melanocortin MC3 and MC5 receptors. The C-terminal segment (Gly10-Lys11-Pro12-Val13) of NDP was clearly important for binding to all the four melanocortin receptor subtypes. The data indicate that the low affinity of gamma-MSH for the melanocortin MC4 receptor is due to its C-terminal (Asp10)-Arg11-Phe12). Substitution of D-Phe7 by D-Nal7 increased the affinity for the melanocortin MC4 receptor but not for the other melanocortin receptor subtypes. The other core residue substitutions lowered the affinity in a differentiated manner for each of the melanocortin receptors. These results are valuable for the molecular modelling and design of selective drugs for the melanocortin receptors.
Schiöth
H B
HB
Department of Pharmaceutical Pharmacology, Uppsala University, Biomedical Center, Sweden. helgis@bmc.uu.se
Mutulis
F
F
Muceniece
R
R
Prusis
P
P
Wikberg
J E
JE
D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D018043:Receptors, Corticotropin / Q000378:metabolism*; D044101:Receptors, Melanocortin; D017386:Sequence Homology, Amino Acid; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism*
D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000521:alpha-MSH