Koerperich, Zoe2023-09-192023-09-192021-05https://hdl.handle.net/11299/257116University of Minnesota Ph.D. dissertation. May 2021. Major: Medicinal Chemistry. Advisor: Carrie Haskell-Luevano. 1 computer file (PDF); xi, 206 pages.The melanocortin receptors are a family of rhodopsin-like (family A) G protein-coupled receptors (GPCRs) that are known to have a variety of conserved physiological functions. The following chapters of this dissertation explore four different projects designed to examine this receptor family through: 1) synthesis of novel ligands using traditional structure activity relationships (SAR), 2) use of a novel mixture based positional scanning approach for ligand discovery, 3) synthesis of endogenous ligand mimetics with established scaffolds, and 4) use of various functional, binding affinity, and proximity assays for in vivo evaluation. Chapter 1 serves as an introduction to the melanocortin receptor (MCR) family as well as ligands (endogenous and synthetic) that are well known in the field. This chapter also introduces the concept of selectivity between the five melanocortin receptors, particularly the centrally expressed melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R). Chapter 2 describes all the materials and methods used in Chapters 3-6 for peptide synthesis, characterization, and pharmacological evaluation. Chapter 3 describes the exploration of single nucleotide polymorphisms in the antagonist signaling molecule Agouti-related Protein (AgRP) by incorporating them into a modified AgRP octapeptide macrocyclic scaffold. Chapter 4 investigates the roles of ligands in protein:protein interactions, specifically those of the MC4R and the kappa opioid receptor (KOR). Chapter 5 demonstrates the complexity involved in designing a selective ligand through focused tetrapeptide SAR and functional assessment in a cAMP accumulation assay. Chapter 6 outlines the discovery of a completely novel MC3R antagonist scaffold using a mixture based positional scanning approach. Lastly, Chapter 7 broadly summarizes the dissertation presented and reflects upon knowledge and experienced gained, advancements to the field, and potential future directions for the work presented in this thesis.enMelanocortinPeptideSARThesis or Dissertation