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melanocortin receptor agonist

Katlyn A Fleming, Katie T Freeman, Mike D Powers, Radleigh G Santos, Ginamarie Debevec, Marc A Giulianotti, Richard A Houghten, Skye R Doering, Clemencia Pinilla, Carrie Haskell-Luevano
The centrally expressed melanocortin-3 and melanocortin-4 receptors (MC3R, MC4R) are established targets to treat diseases of positive and negative energy homeostasis. We previously reported (J. Med. Chem. 60:4342 2017) mixture-based positional scanning approaches to identify dual MC3R agonist and MC4R antagonist tetrapeptides. Herein, 46 tetrapeptides were chosen for MC3R agonist screening selectivity profiles, synthesized, and pharmacologically characterized at the mouse melanocortin-1, -3, -4, and -5 receptors...
February 11, 2019: Journal of Medicinal Chemistry
Rosa Maisto, María Oltra, Lorena Vidal-Gil, Natalia Martínez-Gil, Javier Sancho-Pellúz, Clara Di Filippo, Settimio Rossi, Michele D Amico, Jorge Miguel Barcia, Francisco Javier Romero
ARPE-19 retinal pigment epithelial cells cultured in a medium containing 35 mM D-glucose led to an augmented ROS formation and release of vascular endothelial factor (VEGF)-containing exosomes compared to ARPE-19 cells cultured in a medium containing 5 mM D-glucose (standard medium). Exposing these cells to the melanocortin 5 receptor agonist (MCR5 ) PG-901 (10-10 M), for 9 d reduced ROS generation, the number of exosomes released and their VEGF content. In contrast, incubating the cells with the melanocortin receptor MCR1 agonist BMS-470539 (10-5  M) or with the mixed MCR3/4 agonist MTII (0...
February 9, 2019: Cell Cycle
Peter Kühnen, Heiko Krude, Heike Biebermann
The melanocortin-4 receptor (MC4R) - embedded in the leptin-melanocortin pathway - is activated by proopiomelanocortin (POMC)-derived neuropeptides such as α- and β-melanocyte-stimulating hormone (MSH) and plays an important role in hypothalamic body-weight regulation. Accordingly, MC4R is a potential drug target to combat obesity. Previous attempts to develop MC4R agonists failed due to ineffectiveness or severe adverse events. Recently, a new generation of MC4R ligands was developed. Specifically, setmelanotide was found to be effective by inducing biased signalling of the MC4R and thereby reducing feelings of hunger and leading to substantial weight loss in patients with POMC or leptin receptor deficiency...
January 11, 2019: Trends in Molecular Medicine
Elena Minakova, Jordan Lang, Jesus-Servando Medel-Matus, Georgianna G Gould, Ashley Reynolds, Don Shin, Andrey Mazarati, Raman Sankar
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation...
2019: PloS One
Yingkui Yang, Min Chen, George Ventro, Carroll M Harmon
The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays a key role in regulating adrenocortical function. MC2R is a subtype of the melanocortin receptor family and ACTH is only agonist for MC2R. Our previous result indicates that ACTH1-17 is the minimal peptide required for MC2R activation but DPhe7-ACTH1-17 has no activity at MC2R. In this study, we examined the molecular basis of the MC2R responsible for ligand selectivity using ACTH analogues and MC2R mutagenesis...
December 13, 2018: Molecular and Cellular Endocrinology
Benjamin P Tooke, Hui Yu, Jessica M Adams, Graham L Jones, Talisha Sutton-Kennedy, Lakshmi Mundada, Nathan R Qi, Malcolm J Low, Kavaljit H Chhabra
OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation...
November 20, 2018: Molecular Metabolism
Maria Consiglia Trotta, Rosa Maisto, Nicola Alessio, Anca Hermenean, Michele D'Amico, Clara Di Filippo
The study explored the anti-hypertrophic effect of the melanocortin MC5R stimulation in H9c2 cardiac myocytes exposed to high glucose. This has been done by using α-MSH and selective MC5R agonists and assessing the expression of GLUT4 and GLUT1 transporters, miR-133 and urotensin receptor levels as a marker of cardiac hypertrophy. The study shows for the first time an up-regulation of MC5R expression levels in H9c2 cardiomyocytes exposed to high glucose medium (33 mM D-glucose) for 48 h, compared to cells grown in normal glucose medium (5...
2018: Frontiers in Physiology
Hai-Jie Zhang, Hua-Jie Xie, Wei Wang, Zhi-Qiang Wang, Ya-Xiong Tao
The melanocortin-3 receptor (MC3R) is a member of the G protein-coupled receptor superfamily that plays a critical role in controlling energy balance and metabolism. Although pharmacological characterization of MC3R has been reported previously in several other species, there is no report on the MC3R from giant panda (Ailuropoda melanoleuca). This ancient species is known as a 'living fossil' and is among the most endangered animals in the world. Giant panda survive on a specialized diet of bamboo despite possessing a typical carnivorous digestive system...
October 31, 2018: General and Comparative Endocrinology
Lovisa Bergwall, Hanna Wallentin, Johannes Elvin, Peidi Liu, Roberto Boi, Carina Sihlbom, Kyle Hayes, Dale Wright, Börje Haraldsson, Jenny Nyström, Lisa Buvall
The melanocortin-1 receptor (MC1R) in podocytes has been suggested as the mediator of the ACTH renoprotective effect in patients with nephrotic syndrome with the mechanism of action beeing stabilization of the podocyte actin cytoskeleton. To understand how melanocortin receptors are regulated in nephrotic syndrome and how they are involved in restoration of filtration barrier function, melanocortin receptor expression was evaluated in patients and a rat model of nephrotic syndrome in combination with cell culture analysis...
October 24, 2018: Scientific Reports
Giuseppe Bruschetta, Jung Dae Kim, Sabrina Diano, Li F Chan
OBJECTIVE: Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2. METHODS: To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice...
December 2018: Molecular Metabolism
K Eerola, S Virtanen, L Vähätalo, L Ailanen, M Cai, V Hruby, M Savontaus, E Savontaus
γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition...
October 1, 2018: Journal of Endocrinology
Shengchen Liao, Jingjing Dong, Weina Xu, Bingwen Xi, Yaxiong Tao, Bo Liu, Jun Xie
The melanocortin-5 receptor (MC5R) plays an important role in the regulation of exocrine secretion in mammals. Its function in fish is not well established. In this study, we reported the molecular cloning, tissue expression, and pharmacological characterization of Megalobrama amblycephala MC5R (MamMC5R), as well as the effect of catching stress on its expression. The full-length cDNA of Mammc5r gene was 1237 bp, consisted of a 990-bp open reading frame encoding 329 amino acids. Sequence analyses revealed that the nucleotide and amino acid sequences of Mammc5r were highly homologous (> 90%) with MC5Rs of zebrafish, common carp, and goldfish...
October 4, 2018: Fish Physiology and Biochemistry
S Almeida Scalvino, A Chapelle, N Hajem, E Lati, P Gasser, J-C Choulot, L Michel, M Hocquaux, E Loing, J Attia, J Wdzieczak-Bakala
OBJECTIVE: Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying...
October 2018: International Journal of Cosmetic Science
Ye Ran Yoon, Tae-Gul Lee, Mi-Hyun Choi, Seung Woo Shin, Young-Gyu Ko, Im Joo Rhyu, Dong-Hoon Kim, Je Kyung Seong, Ja-Hyun Baik
The melanocortin-4 receptor (MC4R) belongs to the G protein-coupled receptor (GPCR) family and plays an essential role in the control of energy homeostasis. Here, we identified a novel MC4R-interacting protein, glucose-regulated protein 78 (GRP78), from a pulldown assay using hypothalamic protein extracts and the third intracellular loop of MC4R. We found that MC4R interacted with GRP78 in both the cytosol and at the cell surface and that this interaction increased when MC4R was internalized in the presence of the agonist melanotan-II (MTII)...
September 12, 2018: Experimental & Molecular Medicine
Xiao-Chen Yuan, Ya-Xiong Tao
It is time-consuming and costly to bring new drugs to market, making it necessary and urgent to exploit existing drugs for new uses. Recently, fenoprofen was demonstrated as an allosteric modulator at melanocortin receptors (MCRs), although the exact mode of action has not been clarified. MCRs regulate multiple functions, including pigmentation, adrenal steroidogenesis, inflammation, energy homeostasis, and exocrine gland secretion. In this study, we showed that fenoprofen failed to displace the orthosteric agonist Nle4 -d-Phe7 -α-melanocyte stimulating hormone from binding to MC3-5R while possessing positive allosteric modulator activities at these receptors...
October 11, 2018: ACS Chemical Neuroscience
Ti-Lin Yi, Li-Kun Yang, Guo-Liang Ruan, Dai-Qin Yang, Ya-Xiong Tao
Melanocortin-4 receptor (MC4R) plays critical roles in the regulation of various physiological processes, such as energy homeostasis, reproduction and sexual function, cardiovascular function, and other functions in mammals. Although the functions of the MC4R in fish have not been extensively studied, the importance of MC4R in regulation of piscine energy expenditure and sexual functions is emerging. Swamp eel (Monopterus albus) is an economically and evolutionarily important fish widely distributed in tropics and subtropics...
December 15, 2018: Gene
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
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
Kim Eerola, Siru Virtanen, Laura Vähätalo, Liisa Ailanen, Minying Cai, Victor Hruby, Mikko Savontaus, Eriika Savontaus
γ-melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long-term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R-agonism is dependent on the state of energy balance and nutrition...
July 13, 2018: Journal of Endocrinology
Anthony P Coll
Safe and effective pharmacological treatments for severe obesity remain scarce. In this issue of Cell Metabolism, Iepsen et al. (2018) show that obese patients with pathogenic melanocortin 4 receptor mutations, the most common form of monogenic obesity, lose weight with glucagon-like peptide 1 (GLP-1) receptor agonist therapy.
July 3, 2018: Cell Metabolism
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