Comparative Intracerebroventricular and Intrathecal Administration of a Nanomolar Macrocyclic Melanocortin Receptor Agonist MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro]) Decreases Food Intake in Mice

Abstract

There is a critical need to find safe therapeutics to treat an increasingly obese population and diseases associated with an imbalance in energy homeostasis. The melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) ligands have long been the focus to help scientists understand energy homeostasis and the regulation of feeding behavior. Herein, we use a nanomolar macrocyclic melanocortin receptor agonist ligand MDE6-5-2c (c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro) to examine metabolic and energy hemostasis profiles upon intrathecal (IT) administration directly into the spinal cord as compared to intracerebroventricular (ICV) administration directly into the brain. Overall, central ICV administration of MDE6-5-2c resulted in decreased food intake, in a dose-dependent manner, and decreased respiratory exchange ratio (RER). Comparison of IT versus ICV routes of MDE6-5-2c administration resulted in MDE6-5-2c possessing a longer duration of action on both feeding behavior and RER via IT. The C-peptide, ghrelin, GIP, leptin, IL-6, and resistin plasma hormones and biomarkers were compared using IT versus ICV MDE6-5-2c routes of administration. Plasma resistin levels were decreased upon ICV treatment of MDE6-5-2c, as compared to ICV vehicle control treatment. Intrathecal treatment resulted in significantly decreased inflammatory cytokine interleukin-6 (IL-6) levels compared to ICV administration. Investigation of the nonselective MC3R and MC4R macrocyclic agonist MDE6-5-2c molecule revealed differences in food intake, RER, and plasma biomarker profiles

Discovery of a Pan-Melanocortin Receptor Antagonist [Ac-DPhe(pI)-Arg-Nal(2′)-Orn-NH2] at the MC1R, MC3R, MC4R, and MC5R that Mediates an Increased Feeding Response in Mice and a 40-Fold Selective MC1R Antagonist [Ac-DPhe(pI)-DArg-Nal(2′)-Arg-NH2]

“…This compound was dosed via intrathecal (IT) administration directly into the spinal canal, as previously reported for other melanocortin ligands. 15,68 The IT route was selected to permit direct CNS administration of the tetrapeptide to assess physiological effects of the compound at the target tissue as a proof-of-concept study. The FDA approval of the melanocortin peptide agonist setmelanotide (Imcivree) 35 for weight loss in patients with select genetic conditions as a daily subcutaneous injection suggests that peptide melanocortin drugs may be optimized for alternate administration routes for clinical use.…”

“…An obese phenotype is observed when the MC4R is knocked out in mice . Upon central administration in mice, MC4R agonists decrease and antagonist ligands increase food intake. ,, To probe the potential effects on food intake, tetrapeptide 14 (SSM1-8; Figure ) was selected as a representative compound to examine the potential in vivo effects of this tetrapeptide series. The greater than 10-fold selectivity for 14 (SSM1-8) for the MC4R would support a conclusion that any observed effects on feeding would most likely be mediated by the MC4R.…”

“…This study was conducted in accordance with the guidelines set up by the Institutional Animal Care and Use Committee (IACUC) at the University of Minnesota. Wild-type (WT) male and female mice with a mixed 129/Sv×C57BL/6J background derived from an in house breeding colony were used throughout this experiment, as previously reported in the literature. ,,, Mice were housed in a temperature-controlled room (23–25 °C) and maintained on a reversed 12 h light/dark cycle (lights off at 11:00 am). Mice had ad libitum access to normal chow (Harlan Teklad 2018 Diet: 18.6% crude protein, 6.2% crude fat, 3.5% crude fiber, with energy density of 3.1 kcal/g) and water.…”

Pharmacotherapy in Childhood Obesity

“…In case of activation of the MC4R, which is expressed in the hypothalamus where it regulates feeding behavior as well as in the penile tissue, where it is involved in reproduction, overactivation of the receptor (Fig. 1) by artificial ligands might have multiple effects, which are not always wanted at a time [96][97][98][99].…”

Functional Mixture-Based Positional Scan Identifies a Library of Antagonist Tetrapeptide Sequences (LAtTeS) with Nanomolar Potency for the Melanocortin-4 Receptor and Equipotent with the Endogenous AGRP(86-132) Antagonist

“…The melanocortin system is composed of five G protein-coupled receptors, − endogenous agonists (including α-MSH, β-MSH, γ-MSH, and ACTH) derived from the proopiomelanocortin (POMC) gene transcript, and the naturally occurring antagonists agouti signaling protein (ASP) , and agouti-related protein (AGRP). − The melanocortin receptor (MCR) family is involved in many physiological processes, including pigmentation (MC1R), , steroidogenesis (MC2R), , exocrine gland function in rodents (MC5R), , and energy homeostasis/food intake/obesity/anorexia (MC3R and MC4R). − Selective knockout of the MC4R in mice results in hyperphagia and obesity, with a similar phenotype observed in humans deficient in MC4R signaling. − As the MC4R is one of the central regulators of appetite and body weight, selective ligands for this receptor are highly desirable. Purported MC4R-selective agonist peptide ligands (LY2112688 and setmelanotide − ) have been reported to decrease appetite and food consumption in human trials, although LY2112088 was not advanced due to cardiovascular liabilities .…”