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melanocortin receptor agonist

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...
July 31, 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
Mark D Ericson, Zoe M Koerperich, Katie T Freeman, Katlyn A Fleming, Carrie Haskell-Luevano
The melanocortin-3 and melanocortin-4 receptors (MC3R and MC4R), endogenous agonists derived from the proopiomelanocortin gene transcript, and naturally occurring antagonists agouti and agouti-related protein (AGRP) have been linked to biological pathways associated with energy homeostasis. The active tripeptide sequence of AGRP, Arg111-Phe112-Phe113, is located on a hypothesized β-hairpin loop. Herein, stereochemical modifications of the Arg-Phe-Phe sequence were examined in the octapeptide AGRP-derived macrocyclic scaffold c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was Asn or diaminopropionic acid (Dap)...
July 20, 2018: ACS Chemical Neuroscience
Noureldin Saleh, Gunnar Kleinau, Nicolas Heyder, Timothy Clark, Peter W Hildebrand, Patrick Scheerer
The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site...
2018: Frontiers in Pharmacology
Sid Topiol
The determination of the potential value of receptor trafficking at melanocortin receptors has been hampered by the absence of known biased ligands. Heterobivalent MC4R ligands linking agonist to antagonist small peptidic moieties were designed and found to act as Gαs enhancers while minimally activating β-arrestin recruitment. The strategy invoked offers intriguing promise as a surprising approach that is possibly broadly applicable to the challenge of designing biased ligands at other GPCRs.
June 4, 2018: Journal of Medicinal Chemistry
Eva W Iepsen, Jinyi Zhang, Henrik S Thomsen, Elizaveta L Hansen, Mette Hollensted, Sten Madsbad, Torben Hansen, Jens J Holst, Jens-Christian Holm, Signe S Torekov
Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6...
July 3, 2018: Cell Metabolism
K V Derkach, I B Sukhov, V M Bondareva, A O Shpakov
Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems...
2018: Advances in Gerontology, Uspekhi Gerontologii
Shalini Jain, Anna Panyutin, Naili Liu, Cuiying Xiao, Ramón A Piñol, Priyanka Pundir, Clemence Girardet, Andrew A Butler, Xinzhong Dong, Oksana Gavrilova, Marc L Reitman
Intraperitoneal administration of the melanocortin agonist melanotan II (MTII) to mice causes a profound, transient hypometabolism/hypothermia. It is preserved in mice lacking any one of melanocortin receptors 1, 3, 4, or 5, suggesting a mechanism independent of the canonical melanocortin receptors. Here we show that MTII-induced hypothermia was abolished in KitW-sh/W-sh mice, which lack mast cells, demonstrating that mast cells are required. MRGPRB2 is a receptor that detects many cationic molecules and activates mast cells in an antigen-independent manner...
May 29, 2018: American Journal of Physiology. Endocrinology and Metabolism
Toshihiro Goto, Michiko Itoh, Takayoshi Suganami, Sayaka Kanai, Ibuki Shirakawa, Takeru Sakai, Masahiro Asakawa, Toshihiro Yoneyama, Toshihiro Kai, Yoshihiro Ogawa
Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD). Treatment with OCA effectively prevented chronic inflammation and liver fibrosis in WD-fed MC4R-KO mice with only marginal effect on body weight and hepatic steatosis...
May 25, 2018: Scientific Reports
Brandon Podyma, Hui Sun, Eric A Wilson, Bradley Carlson, Ethan Pritikin, Oksana Gavrilova, Lee S Weinstein, Min Chen
Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein Gs α, but whether Gs α mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous Gs α-inactivating mutations, only develop obesity when the Gs α mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates Gs α imprinting within the central nervous system (CNS) in this disorder...
July 13, 2018: Journal of Biological Chemistry
Aleksandar Todorovic, Cody J Lensing, Jerry Ryan Holder, Joseph W Scott, Nicholas B Sorensen, Carrie Haskell-Luevano
The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1 -dPhe2 -Arg3 -Trp4 -NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R)...
June 11, 2018: ACS Chemical Neuroscience
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
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
Adam J Goldenberg, Ashley L Gehrand, Emily Waples, Mack Jablonski, Brian Hoeynck, Hershel Raff
The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups...
July 1, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Saghar Mowlazadeh Haghighi, Yang Zhou, Jixun Dai, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanoma skin cancer is the fastest growing cancer in the US [1]. A great need exists for improved formulations and mechanisms to prevent and protect human skin from cancers and other skin damage caused by sunlight exposure. Current efforts to prevent UV damage to human skin, which in many cases leads to melanoma and other skin cancers. The primordial melanocortin-1 receptor (MC1R) is involved in regulating skin pigmentation and hair color, which is a natural prevention from UV damage. The endogenous melanocortin agonists induce pigmentation and share a core pharmacophore sequence "His-Phe-Arg-Trp", and it was found that substitution of the Phe by D-Phe results in increasing melanocortin receptor potency...
May 10, 2018: European Journal of Medicinal Chemistry
Cody J Lensing, Katie T Freeman, Sathya M Schnell, Robert C Speth, Adam T Zarth, Carrie Haskell-Luevano
Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore...
May 9, 2018: Journal of Medicinal Chemistry
Francesco Merlino, Yang Zhou, Minying Cai, Alfonso Carotenuto, Ali M Yousif, Diego Brancaccio, Salvatore Di Maro, Silvia Zappavigna, Antonio Limatola, Ettore Novellino, Paolo Grieco, Victor J Hruby
We report the development of macrocyclic melanocortin derivatives of MT-II and SHU-9119, achieved by modifying the cycle dimension and incorporating constrained amino acids in ring-closing. This study culminated in the discovery of novel agonists/antagonists with an unprecedented activity profile by adding pieces to the puzzle of the melanocortin receptor selectivity. Finally, the resulting 19- and 20-membered rings represent a suitable frame for the design of further therapeutic ligands as selective modulators of the melanocortin system...
May 10, 2018: Journal of Medicinal Chemistry
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