Melanocortin ligands: 30 years of structure–activity relationship (SAR) studies

The challenge of peptide and peptidomimetic research is the development of methods and techniques to improve the biological properties of native peptides and to convert peptide ligands into non‐peptide compounds. Improved biological properties of peptides includes enhancement of stability, potency, and receptor selectivity, for both in vivo and in vitro applications. The design of a ligand with specific activity and desired biological properties is a complex task, and, to accomplish this objective, knowledge about putative interactions between a ligand and the corresponding receptor will be valuable. This includes interactions for both the binding and signal transduction processes. Structure–activity relationship (SAR) studies involve systematic modification of a lead peptide and are designed to provide insight into potential interactions involved in the formation of the ligand–receptor complex. It is desirable to have knowledge about both favorable and unfavorable processes that may occur in putative ligand–receptor interactions that result in either receptor stimulation or inhibition. Herein, we discuss various SAR studies that have involved melanocortin peptides over three decades and the information these studies have provided to the melanocortin field. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 325–356, 2004