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 (12c) displayed MC1R selectivity (13-fold and more). An NMR study of 12c 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.