Development of an efficient methodology to identify and mimic the bioactive conformation of a GPCR-binding peptide ligand is described. We designed the cyclopropane-based peptidomimetics that are composed of eight stereoisomers and can mimic various three-dimensional structures of tetrapeptide. The peptidomimetic strategy was applied to design melanocortin receptor (MCR) ligands based on the active residues of the endogenous MCR ligands, i.e. His-Phe-Arg-Trp. The mimetics were synthesized from chiral epichlorohydrin via the diastereoselective Grignard reaction on sulfinylimine as the key step. From the structure-activity relationship study of the eight stereoisomers, mimetic ent-1 was found to mimic the bioactive conformation of the active tetrapeptide moiety. Using ent-1 as a lead, a more potent MC4R ligand ent-1-C4Ph was developed.
