The MC3R and MC4R proteins comprise two melanocortin receptor subtypes that are involved in obesity, with each protein displaying a unique mechanism of action. To enable the design of a selective drug candidate, the solution structures of four peptidyl analogues of the melanocyte stimulating hormones, NDP-MSH, NDP-MSH(4-10) and two cyclic forms ([C5,C10]NDP-MSH(5-10),}NDP-MSH(5-11)]. were characterized by two-dimensional nuclear magnetic resonance(NMR)spectroscopy and simulated annealing calculations. Using data from c-AMP assays in combination with structural analysis of melanocortin receptor/ligand models, we conclude that a lysine residue at the C-terminus Of the His-Phe-Arg-Trp core sequence of melanocortin in hormone is an important determinant for receptor selectivity in the both cyclic and linear MSH analogues, Our results suggest that side-chain orientation and charge-charge interactions with the ligand Molecule play critical roles in receptor selectivity, whereas the overall backbone conformation or turn type contributes mainly to receptor binding. (c) 2005 Elsevier Inc. All rights reserved.