Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin

Abstract

The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs).

The melanocortin receptor signaling system and its role in neuroprotection against neurodegeneration: Therapeutic insights

“…[34][35][36][37] MC3R and MC4R are predominantly expressed in the CNS, and are hence known as neural MCRs. 2 Their alpha-helical TM3 domains include cysteine at the C terminus and have a conserved pattern of aspartic acid-arginine-tyrosine in the junction. 38 The genes for human MCRs are found on autosomal single exons.…”

“…137 Preclinical studies suggest that the melanocortin system may act as a physiological protector in a number of acute and chronic neurodegenerative diseases 16,138 (Figure 4), and targeting the melanocortin system may induce both neuroprotection and neurogenesis. 23 It has been demonstrated that activating the MC4R in astrocytes has strong anti-inflammatory and in vitro neuroprotective effects, indicating that this may be a possible target to reduce continuing neurodegeneration and inflammation in MS. 2 Research showed that setmelanotide, as a highly selective and novel MC4R agonist, improves the reactive phenotype in astrocyte cells and significantly increases the production of interleukin-6 and −11. This effect may be caused by increased phosphorylation of CREB.…”

“…The brain expresses greater levels of all of the MCR subtypes, particularly in the cerebellum, hippocampus, and basal ganglia 34–37 . MC3R and MC4R are predominantly expressed in the CNS, and are hence known as neural MCRs 2 . Their alpha‐helical TM3 domains include cysteine at the C terminus and have a conserved pattern of aspartic acid‐arginine‐tyrosine in the junction 38 .…”

“…MC2R is predominantly located in the adrenal gland, while MC3R and MC4R are generally distributed in the brain and the periphery. 2 Also, MC5R is located all over the body. 3 In addition, the endogenous agouti signaling protein (ASIP) and agouti-related protein (AGRP) are the antagonists of the MCR family.…”

“…The melanocortin 1 receptor (MC1R) is mostly located in the periphery, particularly in the skin. MC2R is predominantly located in the adrenal gland, while MC3R and MC4R are generally distributed in the brain and the periphery 2 . Also, MC5R is located all over the body 3 .…”