Design of cyclic and other templates for potent and selective peptide alpha-MSH analogues

For over three decades, the design of linear peptide ligands often has incorporated cyclic constraints to improve potency, receptor selectivity, proteolytic stability and biodistribution. Its importance has been so well established that modern day schemes for ligand-based drug design often start with cyclization of linear peptides to rigidify peptide structure, to limit its conformational possibilities, and to find key pharmacophore elements in three-dimensional space. In the past several years, cyclic constraints have been used to develop ligands with improved efficacy, binding affinity, biostability and receptor selectivity for alpha-melanocyte-stimulating hormone (alpha-MSH). Furthermore, potent cyclic alpha-MSH analogues, such as MT-II and SHU-9119, have made structure-activity relationship studies and molecular modeling more useful for creating new three-dimensional, topographical pharmacophore templates.