Design and synthesis of novel melanocortin receptor ligands

Melanocortin receptors (MC1R-MC5R) belong to the G-protein coupled receptor superfamily. The interactions of peptide hormones (ACTH, alpha-, beta- and gamma-MSH) with the melanocortin receptors regulate multiple physiological functions in the human body. Pharmacological studies of the melanocortin receptors have revealed very broad biological effects including pigmentation, steroidogenesis, energy homeostasis, thermoregulation, anti-inflammation, nerve regeneration, sexual behavior, feeding behavior and memory, and others. Due to the lack of selectivity of the endogenous ligands (except ACTH) the exact biological roles of the melanocortin receptor subtypes have not been fully elucidated. The objectives of our research are the design and synthesis of new, selective and potent ligands for the melanocortin receptor subtypes to help elucidate their biological functions. Since the three-dimensional structures of the melanocortin receptors and their endogenous ligands are unknown, receptor structure-based design has not been applied. We have chosen a "classical" ligand-based design with the primary structure of an endogenous ligand, gamma-MSH, as a starting point. Our design strategy is to gain high selectivity and potency by fixing the spatial structure of this very flexible peptide ligand in hopes that we can induce the bioactive conformation. We have examined two strategies to constrain the peptide backbone. The first approach is based on global constraint of the peptides by cyclization. A group of 36 cyclic peptides has been synthesized using thioether bond formation as a cyclization step. Macrocyclic peptide ligands varied from 15- to 30-membered rings. The truncated sequence of gamma-MSH has been applied in the cyclic series. In the second strategy we have introduced a local constraint into the peptide backbone similar to a reverse turn structure. We have made a very radical change in ligand conformation by peptide complexation with a transition metal in different positions of the sequence. In this approach we have conserved all amino acid residues of gamma-MSH. All novel modified peptides have been synthesized by solid phase methodology. Preliminary biological studies indicate that we have identified very selective and potent ligands.