TY - JOUR
T1 - Synthesis and activity of the melanocortin Xaa-D-Phe-Arg-Trp-NH2 tetrapeptides with amide bond modifications
AU - Todorovic, A.
AU - Holder, J. R.
AU - Scott, J. W.
AU - Haskell-Luevano, C.
PY - 2004/3
Y1 - 2004/3
N2 - The melanocortin receptor (MCR) pathway has been identified as participating in several physiologically important pathways including pigmentation, energy homeostasis, inflammation, obesity, hypertension, and sexual function. All the endogenous MCR agonists contain a core His-Phe-Arg-Trp sequence identified as important for receptor molecular recognition and stimulation. Several structure-activity studies using the Ac-His-D-Phe-Arg-Trp- NH2 tetrapeptide template have been performed in the context of modifying N-terminal 'capping' groups and amino acid constituents. Herein, we report the synthesis and pharmacologic characterization of modified Xaa-D-Phe-Arg-Trp-NH2 (Xaa = His or Phe) melanocortin tetrapeptides (N-site selective methylation, permethylation, or amide bond reduction) at the mouse MC1, MC3, MC4 and MC5 receptors. The modified peptides generated in this study resulted in equipotent or reduced MCR potency when compared with control ligands. The reduced amide bond analog of the Phe-D-Phe-Arg-Trp-NH2 peptide converted its agonist activity into an antagonistic at the central mMC3 and mMC4 receptors involved in the regulation of energy homeostasis, while retaining full agonist activity at the peripheral MC1 and MC5 receptors.
AB - The melanocortin receptor (MCR) pathway has been identified as participating in several physiologically important pathways including pigmentation, energy homeostasis, inflammation, obesity, hypertension, and sexual function. All the endogenous MCR agonists contain a core His-Phe-Arg-Trp sequence identified as important for receptor molecular recognition and stimulation. Several structure-activity studies using the Ac-His-D-Phe-Arg-Trp- NH2 tetrapeptide template have been performed in the context of modifying N-terminal 'capping' groups and amino acid constituents. Herein, we report the synthesis and pharmacologic characterization of modified Xaa-D-Phe-Arg-Trp-NH2 (Xaa = His or Phe) melanocortin tetrapeptides (N-site selective methylation, permethylation, or amide bond reduction) at the mouse MC1, MC3, MC4 and MC5 receptors. The modified peptides generated in this study resulted in equipotent or reduced MCR potency when compared with control ligands. The reduced amide bond analog of the Phe-D-Phe-Arg-Trp-NH2 peptide converted its agonist activity into an antagonistic at the central mMC3 and mMC4 receptors involved in the regulation of energy homeostasis, while retaining full agonist activity at the peripheral MC1 and MC5 receptors.
KW - Agouti
KW - Melanotropin
KW - N-methylation
KW - Obesity
KW - Reduction
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U2 - 10.1111/j.1399-3011.2004.00137.x
DO - 10.1111/j.1399-3011.2004.00137.x
M3 - Article
C2 - 15049839
AN - SCOPUS:1942438119
VL - 63
SP - 270
EP - 278
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
SN - 1747-0277
IS - 3
ER -