N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.
The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.
Todorovic
Aleksandar
A
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA.
Holder
Jerry Ryan
JR
Bauzo
Rayna M
RM
Scott
Joseph Walker
JW
Kavanagh
Renny
R
Abdel-Malek
Zalfa
Z
Haskell-Luevano
Carrie
C
D000215:Acylation; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008544:Melanocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists; D018043:Receptors, Corticotropin / Q000819:agonists; D044101:Receptors, Melanocortin / Q000819:agonists*; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D008024:Ligands; D009842:Oligopeptides; D020033:Protein Isoforms; D044102:Receptor, Melanocortin, Type 1; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; C493001:histidyl-phenylalanyl-arginyl-tryptophanamide; C086971:melanocortin 5 receptor; D014442:Monophenol Monooxygenase