Putative involvement of the hMC3 receptor in feeding behavior and energy homeostasis provides a significant impetus for the development of novel highly selective hMC3R agonists and antagonists. A series of cyclic disulfide peptides with the general sequence of Ac-c[Cys-Arg-Phe-Cys]-Trp-NH₂ was designed as hybrids of the melanocyte-stimulating hormone (MSH) pharmacophore (His-Phe-Arg-Trp) and the Agouti-related protein (AgRP) pharmacophore (Arg-Phe-Phe-Asn). The Arg-Phe residues are hypothesized to be in the center of a β-turn structure, which is constrained with a disulfide bridge. The synthesis of the designed peptides involved a solid-phase construction of the amino acid sequence, and a cyclization via solution-phase air oxidation in the 0.01 M ammonium acetate buffer (pH 7.5). The D-amino acid scan of this new template revealed several analogues, which exhibited potent binding affinity toward the human melanocortin-3 receptor (IC₅₀ = 14-112 nM) as well as excellent selectivity (up to 700-fold). These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.