Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

We
report the development of macrocyclic melanocortin derivatives
of MT-II and SHU-9119, achieved by modifying the cycle dimension and
incorporating constrained amino acids in ring-closing. This study
culminated in the discovery of novel agonists/antagonists with an
unprecedented activity profile by adding pieces to the puzzle of the
melanocortin receptor selectivity. Finally, the resulting 19- and
20-membered rings represent a suitable frame for the design of further
therapeutic ligands as selective modulators of the melanocortin system.