RM-493, a Melanocortin-4 Receptor (MC4R) Agonist, Increases Resting Energy Expenditure in Obese Individuals

Chen, Kong Y.; Muniyappa, Ranganath; Abel, Brent S.; Mullins, Katherine; Staker, Pamela; Brychta, Robert J.; Zhao, Xiongce; Ring, Michael; Psota, Tricia; Cone, Roger D.; Panaro, Brandon L.; Gottesdiener, Keith; Ploeg, Lex H.T. Van der; Reitman, Marc L.; Skarulis, Monica C.

doi:10.1210/jc.2014-4024

Cited by 146 publications

(95 citation statements)

References 27 publications

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“…Unfortunately, most attempts have failed due to safety issues, particularly a negative impact on the cardiovascular system (Fani et al, 2014). Encouragingly, however, a recently developed selective MC4R agonist (setmelanotide) was reported to reverse obesity in monkeys and humans without compromising cardiovascular safety (Chen et al, 2015; Kievit et al, 2013). This same compound was recently employed to successfully treat human POMC deficiency (Kühnen et al, 2016).…”

Section: Therapeutic Applications: Emerging Treatment Avenues For Metmentioning

confidence: 99%

Gut-Brain Cross-Talk in Metabolic Control

Clemmensen

Müller

Woods

et al. 2017

Cell

233

157

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Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

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Section: Therapeutic Applications: Emerging Treatment Avenues For Metmentioning

confidence: 99%

Gut-Brain Cross-Talk in Metabolic Control

Clemmensen

Müller

Woods

et al. 2017

Cell

233

157

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“…The parent SFTI-1 scaffold adopts a highly rigid and well-defined 3D structure characterized by two short β -strands connected via a type I β -turn ( 10 FPDG 13 , 1 ) and an extended ω -turn ( 2 TKSIPPI 8 ). 19 The three proline residues of SFTI-1 adopt well-defined conformations: the Ile5-Pro6 peptide bond is in a cis conformation, whereas Pro6-Pro7 and Phe10-Pro11 are in trans conformations.…”

Section: Resultsmentioning

confidence: 99%

“…5 One strategy that has proven particularly successful is to conformationally constrain the tetrapeptide pharmacophore (typically through side chain-to-side chain cyclization), thereby reducing conformational flexibility and minimizing entropic losses upon receptor binding. This approach has resulted in highly potent (IC 50 /EC 50 : pM) MCR ligands, including melanotan (MT)-I and -II, 7 RM493, 8 and bremelanotan (Pt-141). 9 However, despite their high potency, the MCR subtype selectivity of these molecules is modest.…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1

et al. 2018

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Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3–5R. Double N-methylated compound 18 showed a pKi of 8.73 ± 0.08 (Ki = 1.92 ± 0.34 nM) and a pEC50 of 9.13 ± 0.04 (EC50 = 0.75 ± 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N-methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery.

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“…The α-MSH analog RM-493 [43,44], also known as setmelanotide, was awarded orphan drug status for POMC deficiency and Prader-Willi syndrome [37].…”

Section: Pomc Deficiency (Omim #609734)mentioning

confidence: 99%

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

Stagi¹,

Bianconi²,

Sammarco³

et al. 2017

Adiposity - Omics and Molecular Understanding

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Historically, some genetic syndromes and monogenic forms of obesity have been identified by clinical features and by sequencing candidate genes in patients with severe obesity. The phenotypic expression of genetic factors involved in obesity is variable, thereby allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. Many of the findings emerged from studying families who displayed a classical Mendelian pattern of inheritance. On the contrary, patients with syndromic obesity show a various degree of intellectual disability, different dysmorphic features, and organ-specific abnormalities. But to date, not all involved genes have been identified so far. New diagnostic tools, such as genome-wide studies, array CGH, and whole-exome sequencing, have highlighted more complex models of inheritance, and even more candidate genes were identified. This increase of knowledge may provide insights into the mechanisms involved in the regulation of body weight and finally lead to specific treatments. In these patients, hyperphagia is often a primary phenotypic component. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present today with a lack of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. We have evaluated retrospectively the literature data on weight, body mass index (BMI), clinical features, treatments, and treatment response in pediatric patients with forms of genetic obesity. However, this chapter provides an updated picture of emerging knowledge outlined by the more comprehensive genetic approaches, trying to outline more candidate genes for these forms of genetic obesity. Relevant papers will be identified through systematic searches of the PubMed, EMBASE and Cochrane databases. All published studies in the English language concerning these disorders will be evaluated. Keywords in the

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RM-493, a Melanocortin-4 Receptor (MC4R) Agonist, Increases Resting Energy Expenditure in Obese Individuals

Abstract: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.

Cited by 146 publications

References 27 publications

Gut-Brain Cross-Talk in Metabolic Control

Gut-Brain Cross-Talk in Metabolic Control

Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1

New Thoughts on Pediatric Genetic Obesity: Pathogenesis, Clinical Characteristics and Treatment Approach

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