Melanocortin-4 Receptor Modulators for the Treatment of Obesity: a Patent Analysis (2008–2014)

Lee, Esther C.Y.; Carpino, Philip A.

doi:10.4155/ppa.15.1

Cited by 9 publications

(10 citation statements)

References 45 publications

(51 reference statements)

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“…Indeed, MC4R mutations represent the most prevalent form of monogenic obesity (0.5–6% of obese individuals) 52 , and MC4R variations are highly correlated with fat mass 128 . However, contrasting this pathological association is the potential of the MC4R as a pharmacotherapeutic target for obesity 129,130 . Consistent with rodent studies, pharmacological compounds that augment MC4R signaling promote appetite suppression and weight loss in humans 130 .…”

Section: Mc4r Pharmacotherapymentioning

confidence: 99%

“…Consistent with rodent studies, pharmacological compounds that augment MC4R signaling promote appetite suppression and weight loss in humans 130 . Unfortunately, these drugs influence other MC4R-regulated processes, such as cardiovascular tone, sexual function and pandiculation, limiting their clinical application 129 . At present only one MC4R compound, setmelanotide (RM-493; Rhythm Pharmaceuticals), is undergoing clinical trials, and only for use in the rare obesity conditions Prader-Willi syndrome and POMC deficiency.…”

Section: Mc4r Pharmacotherapymentioning

confidence: 99%

“…In obese rhesus macaques 132 and a small cohort of obese humans 133 , this drug had no adverse effects on blood pressure; however, the latter study reported sexual side effects 133 . Alternative strategies such as positive allosteric modulators (PAMs), which augment MC4R signaling upon orthosteric binding of α-MSH, and molecular chaperones, which increase cell surface availability of MC4Rs, are being investigated as a means of enhancing the efficacy of endogenous α-MSH to offer more physiologically relevant temporal specificity 129 .…”

Section: Mc4r Pharmacotherapymentioning

confidence: 99%

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Melanocortin-4 receptor–regulated energy homeostasis

2016

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The melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components—two antagonistically acting ligands and two cognate receptors—this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the melanocortin-4 receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis.

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Section: Mc4r Pharmacotherapymentioning

confidence: 99%

Section: Mc4r Pharmacotherapymentioning

confidence: 99%

Section: Mc4r Pharmacotherapymentioning

confidence: 99%

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Melanocortin-4 receptor–regulated energy homeostasis

2016

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“…The development of MC4R-selective ligands for the treatment of common dietary obesity has so far not resulted in an approved drug, although the nonselective MC4R agonist setmelanotide is currently under priority review at the FDA for certain forms of syndromic obesity. 10,11 Despite intense research efforts in both academia and industry, there remains a need for potent, selective, and stable (ant)agonist ligands for the melanocortin receptors. So far, efforts have focused on variations of known ligands, but the structural requirements for designing receptor-selective ligands are still not straightforward to unravel.…”

Section: ■ Introductionmentioning

confidence: 99%

Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure

et al. 2020

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The melanocortin receptors (MC1R–MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle4-c[Asp5-His6-DNal(2′)7-Arg8-Trp9-Lys10]-NH2). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle4, DNal(2′)7, and Trp9 residues in SHU-9119, as well as the amide linkage between the Asp5 and Lys10 side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.

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“…Currently, there are estimated to be more than 650 million adults with obesity worldwide (25). As obesity is related to different comorbidities such as diabetes mellitus type 2 or cardiovascular disease (26), there is considerable medical, pharmacological, as well as economic interest concerning this receptor (27). The design of highly selective and potent MC4R ligands (28, 29) should be a tool to counteract specifically against obesity (9, 30), which also needs a comprehensive understanding of this receptor under structural-functional perspectives.…”

Section: Introductionmentioning

confidence: 99%

Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective

et al. 2019

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The melanocortin-4 receptor (MC4R) can be endogenously activated by binding of melanocyte-stimulating hormones (MSH), which mediates anorexigenic effects. In contrast, the agouti-related peptide (AgRP) acts as an endogenous inverse agonist and suppresses ligand-independent basal signaling activity (orexigenic effects). Binding of ligands to MC4R leads to the activation of different G-protein subtypes or arrestin and concomitant signaling pathways. This receptor is a key protein in the hypothalamic regulation of food intake and energy expenditure and naturally-occurring inactivating MC4R variants are the most frequent cause of monogenic obesity. In general, obesity is a growing problem on a global scale and is of social, medical, and economic relevance. A significant goal is to develop optimized pharmacological tools targeting MC4R without adverse effects. To date, this has not been achieved because of inter alia non-selective ligands across the five functionally different MCR subtypes (MC1-5R). This motivates further investigation of (i) the three-dimensional MC4R structure, (ii) binding mechanisms of various ligands, and (iii) the molecular transfer process of signal transduction, with the aim of understanding how structural features are linked with functional-physiological aspects. Unfortunately, experimentally elucidated structural information is not yet available for the MC receptors, a group of class A G-protein coupled receptors (GPCRs). We, therefore, generated MC4R homology models and complexes with interacting partners to describe approximate structural properties associated with signaling mechanisms. In addition, molecular insights from pathogenic mutations were incorporated to discriminate more precisely their individual malfunction of the signal transfer mechanism.

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Melanocortin-4 Receptor Modulators for the Treatment of Obesity: a Patent Analysis (2008–2014)

Cited by 9 publications

References 45 publications

Melanocortin-4 receptor–regulated energy homeostasis

Melanocortin-4 receptor–regulated energy homeostasis

Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure

Signal Transduction and Pathogenic Modifications at the Melanocortin-4 Receptor: A Structural Perspective

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