Browsing by Subject "Melanocortin"
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Item Bivalent Ligands as Pharmacological Probes for The Melanocortin Receptors: The Bivalent Advantage(2017-05) Lensing, CodyPharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer’s disease, social disorders, cachexia, and obesity. Of interest to our laboratory is the melanocortin system’s role in energy homeostasis that is mediated through the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R). Specifically, our laboratory focuses on the development of novel pharmacological probes to better understand the role of the melanocortin receptor system’s effects on energy homeostasis. This thesis provides the field with foundational work addressing the functional effects of melanocortin bivalent ligands both in vitro and in vivo. In Chapter 3 and Chapter 4, traditional homobivalent approaches are utilized. The synthesis and in vitro evaluation of homobivalent ligands are discussed in Chapter 3. Lead ligands (CJL-1-87 and CJL-1-31) increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts depending on the specific melanocortin receptor subtype assayed. In Chapter 4, the in vivo effects of lead ligand CJL-1-87 is characterized thoroughly. Bivalent ligand CJL-1-87 had noteworthy advantages as an anti-obesity probe over its monovalent counterpart in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2 to 8 hours after treatment). Further energy expenditure parameters are explored, and possible mechanisms are discussed. In Chapter 5 and Chapter 6, uncommon approaches are attempted to exploit melanocortin dimers to elicited undiscovered pharmacological effects. In the Chapter 5, we present melanocortin unmatched bivalent ligands (MUmBLs) as tools for studying asymmetric function of melanocortin receptor homodimers. MUmBLs contain one agonist scaffold and one antagonist scaffold designed to target a melanocortin homodimer pair such that one receptor is occupied by an agonist scaffold and the other receptor by an antagonist scaffold. Utilizing this design strategy to target the MC4R, first in class biased unmatched bivalent ligands (BUmBLs) were discovered. The BUmBLs displayed biased agonism in which they potently stimulated cAMP signaling, but resulted in minimal activation of the β-arrestin recruitment pathway. In Chapter 6, we describe two different approaches that were pursued to further study melanocortin bivalent ligands’ structure activity relationship (SAR). Homobivalent ligands were designed with 13, 16, 19, 20, and 22 atom linkers to explore the effects of linker length. Overall, these studies resulted in a “flat” SAR in which the compounds all have similar potencies and efficacies. Bivalent ligands were also designed to include the retro-inverso tetrapeptide scaffold DTrp-DArg-Phe-DHis. Although this scaffold lacked high binding affinity and potency, it was very metabolically stable. The incorporation of this scaffold into bivalent ligands yielded ligands with varying potencies and metabolic stabilities. The current discoveries may be broadly applicable to other GPCR systems. As the physiological relevancy to GPCR oligomerization is elucidated, the current medicinal chemistry strategies presented in this thesis should aid in the discovery of probes and possible therapeutics for the further understanding of GPCR pharmacology for various systems.Item Discovery of Peptide and Peptidomimetic Based Ligands Targeting the Melanocortin Receptors: A campaign in mixture-based positional scanning, chemical topology, and structure-activity relationships(2016-07) Doering, SkyeDespite aggressive public health initiatives over the last few decades, the proportion of the population who are obese and overweight continues to expand at an alarming rate. A multitude of external factors, such as easily accessible high-calorie foods and an overall lack of physical activity, are contributing to this epidemic; however, the basic regulatory pathways within the body are not completely understood. Evidence suggests many of the signaling systems regulating energy homeostasis feed into the brain and the final step is mediated by the melanocortin receptors. It has been demonstrated that melanocortin agonists decrease food intake whereas melanocortin antagonists increase food intake when administrated centrally (Nature, 1997, 165-8). Out of the two centrally expressed receptors, it has been hypothesized the melanocortin-4 receptor (MC4R) effects immediate satiety whereas the melanocortin-3 receptor (MC3R) effects the long-term energy needs and food consumption in the body. In order to test this hypothesis there is a need for melanocortin-3 receptor selective compounds which currently do not exist. The work reported within this dissertation lead to the discovery of new dual MC3R agonist/MC4R antagonist ligands in addition to MC3R antagonist ligands selective for the MC3R over the MC4R. These novel ligands were based on new tetrapeptide templates which were identified via mixture-based positional scanning and classic structure-activity relationship studies. This work was supported by NIH grant R01DK091906.Item A Solution Towards Weight Management: Discovery, Design, Synthesis, and Characterization of Melanocortin Ligands(2021-05) Koerperich, ZoeThe 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.Item Tetrapeptide Melanocortin Agonist Ligands Exploring Selectivity of the mMC3R Using DPhe Substitutions in the Ac-His-Arg-DPhe-Tic-NH2 Scaffold(2018-03) Schlasner, KatherineThere are five melanocortin receptors (MC1R-MC5R) that primarily activate the signaling pathway for adenylate cyclase. While both the MC3R and MC4R are hypothesized to be involved in regulating energy homeostasis, the MC3R functionality has been elusive to characterize due to the lack of MC3R-selective ligands. The melanocortin system may be a target for treating obesity or cachexia. When centrally delivered through intracerebroventricular administration, agonists decrease food intake, while antagonists increase food intake. Previous weight management therapies have focused on targeting the MC4R, though off-target cardiovascular effects may limit the clinical utility of these ligands. Therefore, obtaining a MC3R selective compound may allow for a weight regulation therapy that will not have the same cardiovascular liabilities. MC4R-selective ligands have been heavily investigated, however MC3R-selective ligands have largely gone unexplored. A mixture-based positional scan was conducted to generate scaffolds with MC3R selectivity. The lead compound from the study was Ac-His-Arg-(pI)DPhe-Tic-NH2, an MC3R agonist and an MC4R antagonist. The scaffold reverses the sequence of arginine and phenylalanine residues in the His-Phe-Arg-Trp conserved sequence found in endogenous melanocortin ligands1. This work presents a follow-up study investigating the position of the phenylalanine residue in efforts to create a MC3R selective agonist with decreased MC4R antagonist activity.