Pharmacological 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.
University of Minnesota Ph.D. dissertation. May 2017. Major: Medicinal Chemistry. Advisor: Carrie Haskell-Luevano. 1 computer file (PDF); xvii, 308 pages.
Bivalent Ligands as Pharmacological Probes for The Melanocortin Receptors: The Bivalent Advantage.
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