Introduction The natural melanotropin peptides, which include -, -, -melanocyte-stimulating hormone (MSH), and adrenocorticotropin (ACTH), are derived by posttranslational processing of the pro-opiomelanocortin (POMC) gene transcript. Each of them possesses a central “core” sequence His-Phe-Arg-Trp, which is essential for their agonist biological activity. It has been discovered that the melanocortin receptors (hMCR) and their ligands control a surprisingly large number of multifaceted biological actions including skin pigmentation, erectile function, blood pressure and heart rate, control of feeding behavior, and effects on memory and learning processes [1,2]. Of particular interest for pharmaceutical research are the hMC3R and the hMC4R, which have been implicated to play complementary roles in weight control [3]. Therefore, selective ligands for these receptors may provide a novel approach in the treatment of obesity, anorexia, weight loss, and related disorders. Recent reports [4] have shown that some 21-membered or larger cyclic lactam analogs of and -MSH are potent and hMC4R-selective agonists. At the same time, Kavarana et al. [5] have found that enhancing the hydrophobicity of the cyclic peptide combined with the increased ring size resulted in improved hMC3R selectivity. From these observations, we designed a series of novel cyclic -MSH analogs with the following general sequence: c[Nle-Xaa-D-Phe/D-Nal(2’)-Arg-TrpGlu]-NH2. We introduced a bulky hydrophobic residue (Nle ) in the close proximity to the pharmacophore (Xaa-D-Phe/D-Nal(2’)-Arg-Trp) to investigate the impact of steric hindrance on receptor selectivity. Also, a variety of amino acids with a broad range of hydrophobic/hydrophilic properties were placed in position 5 to further explore their complementary role in receptor selectivity (Fig. 1).