Modified melanocortin tetrapeptide Ac-His-dPhe-Arg-Trp-NH at the arginine side chain with ureas and thioureas.
The Ac-His-dPhe-Arg-Trp-NH2 tetrapeptide is a nonselective melanocortin agonist and replacement of Arg in the tetrapeptide with acidic, basic or neutral amino acids results in reduced potency at the melanocortin receptor (MCR) isoforms (MC1R and MC3-5R). To determine the importance of the positive charge and the guanidine moiety for melanocortin activity, a series of urea- and thiourea-substituted tetrapeptides were designed. Replacement of Arg with Lys or ornithine reduced agonist activity at the mouse mMC1 and mMC3-5 receptors, thus supporting the hypothesis that the guanidine moiety is important for receptor potency, particularly at the MC3-5 receptors. The Arg side chain-modified tetrapeptides examined in this study include substituted phenyl, naphthyl, and aliphatic urea and thiourea residues using a Lys side-chain template. These ligands elicit full-agonist pharmacology at the mouse MCRs examined in this study.
Joseph
C G
CG
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
Sorensen
N B
NB
Wood
M S
MS
Xiang
Z
Z
Moore
M C
MC
Haskell-Luevano
C
C
D000818:Animals; D001120:Arginine / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D051379:Mice; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D044101:Receptors, Melanocortin / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry* / Q000494:pharmacology; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology
D009842:Oligopeptides; D044101:Receptors, Melanocortin; C459203:acetyl-histidyl-phenylalanyl-arginyl-tryptophanamide; D014508:Urea; D001120:Arginine; D013890:Thiourea