Human melanin-concentrating hormone (hMCH) is a nonselective natural ligand for the human melanin-concentrating hormone receptors: hMCH-1R and hMCH-2R. Similarly, the smaller peptide encompassing the disulfide ring and 50 ؍ 47 nM) with more than 200-fold selectivity with respect to hMCH-2R. Apparently, these structural changes in positions 6 and 10 results in peptide conformations that allow for efficient interactions with hMCH-1R but are unfavorable for molecular recognition at hMCH-2R.In the last couple of years, melanin-concentrating hormone (MCH) 1 emerged as an important regulator of feeding behavior in rodents (1-7). Similarly to neuropeptide Y, this hormone stimulates appetite in rats when injected intracerebroventricularly, and this orexigenic effect is inhibited by anorectic peptides such as ␣-melanocyte stimulating hormone, glucagon-like peptide 1, and neurotensin (1-7). Additionally, in the hypothalamus of genetically obese (ob/ob) and fasting mice, the level of MCH messenger RNA is elevated, and the metabolic rate of mice lacking MCH is increased. MCH (see Structure 1 for human/rat MCH) also appears to be involved in other biological functions such as regulation of the hypothalamic-pituitarythyroid axis. In humans, this 19-amino acid cyclic peptide is found in the brain, in the lateral hypothalamus and the zona incerta, and acts through specific receptors (8 -12). At present, two receptors are known with which hMCH interacts: hMCH-1R and hMCH-2R (13-23). These receptors are members of the family of G-protein-coupled receptors and their activation leads to mobilization of intracellular calcium. Binding of hMCH to hMCH-1R results in reduction of forskolin-elevated cyclic AMP levels, but binding to hMCH-2R does not cause this effect. The physiological role of hMCH-2R is less well understood than the physiological role of hMCH-1R, but the presence of the MCH-2R messenger RNA in the brain regions implicated in the regulation of body weight suggests that this receptor might also be involved in the regulation of feeding behavior (19 -23).To understand and separate the physiological functions of the MCH receptors, selective agonists are required, because hMCH is a nonspecific natural ligand for both hMCH-1R and hMCH-2R. Similarly, the synthetic ligands reported in the literature do not distinguish between the receptors (13-23).Our previous structure-function studies on hMCH yielded a cyclic peptide consisting of the disulfide ring and Arg 6 of hMCH: the so-called "active core" of hMCH with the four residues, Arg 6 , Met 8 , Arg 11 , and Tyr 13 , critical for molecular recognition at hMCH-1R and hMCH-2R (24 -27). This compound, Ac-hMCH(6 -16)-NH 2 (Structure 2), was equipotent to the fulllength hMCH at both receptors. Moreover, at hMCH-1R, an analog of Ac-hMCH(6 -16)-NH 2 with D-Arg in position 6 was as potent as the parent compound, but, at hMCH-2R, this analog was a noticeably weaker agonist. The D-Arg 6 compound was the first described peptide agonist with enhanced hMCH-1R selectivity with respect to ...