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Setmelanotide

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https://www.readbyqxmd.com/read/30048591/insights-into-the-allosteric-mechanism-of-setmelanotide-rm-493-as-a-potent-and-first-in-class-melanocortin-4-receptor-mc4r-agonist-to-treat-rare-genetic-disorders-of-obesity-through-an-in-silico-approach
#1
Bethany A Falls, Yan Zhang
Human melanocortin-4 receptor (hMC4R) mutations have been implicated as the cause for about 6-8% of all severe obesity cases. Drug-like molecules that are able to rescue the functional activity of mutated receptors are highly desirable to combat genetic obesity among this population of patients. One such molecule is the selective MC4R agonist RM-493 (setmelanotide). While this molecule has been shown to activate mutated receptors with 20-fold higher potency over the endogenous agonist, little is known about its binding mode and how it effectively interacts with hMC4R despite the presence of mutations...
August 13, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/30014268/centrally-acting-agents-for-obesity-past-present-and-future
#2
REVIEW
Ann A Coulter, Candida J Rebello, Frank L Greenway
For many years, obesity was believed to be a condition of overeating that could be resolved through counseling and short-term drug treatment. Obesity was not recognized as a chronic disease until 1985 by the scientific community, and 2013 by the medical community. Pharmacotherapy for obesity has advanced remarkably since the first class of drugs, amphetamines, were approved for short-term use. Most amphetamines were removed from the obesity market due to adverse events and potential for addiction, and it became apparent that obesity pharmacotherapies were needed that could safely be administered over the long term...
July 2018: Drugs
https://www.readbyqxmd.com/read/29736023/mc4r-agonism-promotes-durable-weight-loss-in-patients-with-leptin-receptor-deficiency
#3
Karine Clément, Heike Biebermann, I Sadaf Farooqi, Lex Van der Ploeg, Barbara Wolters, Christine Poitou, Lia Puder, Fred Fiedorek, Keith Gottesdiener, Gunnar Kleinau, Nicolas Heyder, Patrick Scheerer, Ulrike Blume-Peytavi, Irina Jahnke, Shubh Sharma, Jacek Mokrosinski, Susanna Wiegand, Anne Müller, Katja Weiß, Knut Mai, Joachim Spranger, Annette Grüters, Oliver Blankenstein, Heiko Krude, Peter Kühnen
Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants...
May 2018: Nature Medicine
https://www.readbyqxmd.com/read/29726959/melanocortin-4-receptor-pathway-dysfunction-in-obesity-patient-stratification-aimed-at-mc4r-agonist-treatment
#4
Kristin L Ayers, Benjamin S Glicksberg, Alastair S Garfield, Simonne Longerich, Joseph A White, Pengwei Yang, Lei Du, Thomas W Chittenden, Jeffery R Gulcher, Sophie Roy, Fred Fiedorek, Keith Gottesdiener, Sarah Cohen, Kari E North, Eric E Schadt, Shuyu D Li, Rong Chen, Lex H T Van der Ploeg
Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants...
July 1, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29504049/future-pharmacotherapy-for-obesity-new-anti-obesity-drugs-on-the-horizon
#5
REVIEW
Gitanjali Srivastava, Caroline Apovian
PURPOSE OF REVIEW: Obesity is a global health crisis with detrimental effects on all organ systems leading to worsening disease state and rising costs of care. Persons with obesity failing lifestyle therapies need to be escalated to appropriate pharmacological treatment modalities, medical devices, and/or bariatric surgery if criteria are met and more aggressive intervention is needed. The progression of severe obesity in the patient population coupled with related co-morbidities necessitates the development of novel therapies for the treatment of obesity...
June 2018: Current Obesity Reports
https://www.readbyqxmd.com/read/29031731/evaluation-of-a-melanocortin-4-receptor-mc4r-agonist-setmelanotide-in-mc4r-deficiency
#6
Tinh-Hai Collet, Béatrice Dubern, Jacek Mokrosinski, Hillori Connors, Julia M Keogh, Edson Mendes de Oliveira, Elana Henning, Christine Poitou-Bernert, Jean-Michel Oppert, Patrick Tounian, Florence Marchelli, Rohia Alili, Johanne Le Beyec, Dominique Pépin, Jean-Marc Lacorte, Andrew Gottesdiener, Rebecca Bounds, Shubh Sharma, Cathy Folster, Bart Henderson, Stephen O'Rahilly, Elizabeth Stoner, Keith Gottesdiener, Brandon L Panaro, Roger D Cone, Karine Clément, I Sadaf Farooqi, Lex H T Van der Ploeg
OBJECTIVE: Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. METHODS: We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial...
October 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/27468060/proopiomelanocortin-deficiency-treated-with-a-melanocortin-4-receptor-agonist
#7
Peter Kühnen, Karine Clément, Susanna Wiegand, Oliver Blankenstein, Keith Gottesdiener, Lea L Martini, Knut Mai, Ulrike Blume-Peytavi, Annette Grüters, Heiko Krude
Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist...
July 21, 2016: New England Journal of Medicine
https://www.readbyqxmd.com/read/27452145/metabolic-precision-medicines-curing-pomc-deficiency
#8
Timo D Müller, Matthias H Tschöp, Stephen O'Rahilly
Pro-opiomelanocortin deficiency is a rare cause of severe intractable obesity. Two patients have experienced dramatic weight loss in response to setmelanotide, a melanocortin-4 receptor activator. The drug has potential in broader populations, but caution is warranted as it may act at other melanocortin receptors.
August 9, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/27339818/magel2-null-mice-are-hyper-responsive-to-setmelanotide-a-melanocortin-4-receptor-agonist
#9
Jocelyn M Bischof, Lex H T Van Der Ploeg, William F Colmers, Rachel Wevrick
BACKGROUND AND PURPOSE: α- and β-melanocyte-stimulating hormones (MSH) are derived from pro-opiomelanocortin (POMC) and are the natural agonist ligands of the melanocortin 4 receptor, a key regulator of energy homeostasis. Recent rodent and human data have implicated the MAGEL2 gene, which may regulate activation of POMC neurons, as a significant contributor to the metabolic symptoms observed in Prader-Willi Syndrome (PWS). Firstly, patients with protein truncating mutations in MAGEL2 exhibit numerous clinical characteristics of PWS...
September 2016: British Journal of Pharmacology
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