N-alkylated dipeptide amides and related structures as imitations of the melanocortins' active core.
Thirty-three low molecular mass structures combining both peptide and peptoid features were prepared and tested on human melanocortin receptors MC1,3-5R. Most of them displayed low micromolar activity with preference for diamines, guanidino and 2-naphthyl derivatives compared to monoacetylated, amino and 3-indolyl counterparts. Some contained L- or D-histidine residues, but the change did not influence affinity. QSAR modelling yielded excellent models for the MC3-5 receptors explaining R2Y=0.89-0.91 and predicting Q2=0.77-0.80 of the affinity variations. One compound displayed MC1R selectivity (13-fold and more). An NMR study of showed that it exists as a mixture of four rotamers at its tertiary amide bonds. Comparisons with earlier data for melanocortin core tetrapeptide analogues indicate that the novel peptide-peptoids interact with the melanocortin receptors in a different way.
Department of Pharmaceutical Biosciences, Division of Pharmacology, Uppsala University, Box 591, Biomedicum, SE-751 24 Uppsala, Sweden.
Felikss
F
Mutulis
Ilze
I
Mutule
Edvards
E
Liepinsh
Aleh
A
Yahorau
Maris
M
Lapinsh
Sergei
S
Kopantshuk
Santa
S
Veiksina
Ago
A
Rinken
Jarl E S
JE
Wikberg
D000478:Alkylation; D000577:Amides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D021281:Quantitative Structure-Activity Relationship; D044101:Receptors, Melanocortin / Q000737:chemistry / Q000378:metabolism*; D018411:Spodoptera
D000577:Amides; D004151:Dipeptides; D044101:Receptors, Melanocortin