keyword
https://read.qxmd.com/read/37627313/divergent-pharmacology-and-biased-signaling-of-the-four-melanocortin-4-receptor-isoforms-in-rainbow-trout-oncorhynchus-mykiss
#21
JOURNAL ARTICLE
Ren-Lei Ji, Ting Liu, Zhi-Shuai Hou, Hai-Shen Wen, Ya-Xiong Tao
The melanocortin-4 receptor (MC4R) is essential for the modulation of energy balance and reproduction in both fish and mammals. Rainbow trout ( Oncorhynchus mykiss ) has been extensively studied in various fields and provides a unique opportunity to investigate divergent physiological roles of paralogues. Herein we identified four trout mc4r ( mc4ra1 , mc4ra2 , mc4rb1 , and mc4rb2 ) genes. Four trout Mc4rs (omMc4rs) were homologous to those of teleost and mammalian MC4Rs. Multiple sequence alignments, a phylogenetic tree, chromosomal synteny analyses, and pharmacological studies showed that trout mc4r genes may have undergone different evolutionary processes...
August 16, 2023: Biomolecules
https://read.qxmd.com/read/37589099/azetidines-with-all-carbon-quaternary-centers-merging-relay-catalysis-with-strain-release-functionalization
#22
JOURNAL ARTICLE
Che-Ming Hsu, Heng-Bo Lin, Xin-Zhi Hou, Radyn Vanessa Phaz P Tapales, Chen-Kuei Shih, Shinje Miñoza, Yu-Syuan Tsai, Zong-Nan Tsai, Cheng-Lin Chan, Hsuan-Hung Liao
Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp2 -Csp3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility...
August 17, 2023: Journal of the American Chemical Society
https://read.qxmd.com/read/37524700/structural-insights-into-ligand-recognition-and-subtype-selectivity-of-the-human-melanocortin-3-and-melanocortin-5-receptors
#23
JOURNAL ARTICLE
Wenbo Feng, Qingtong Zhou, Xianyue Chen, Antao Dai, Xiaoqing Cai, Xiao Liu, Fenghui Zhao, Yan Chen, Chenyu Ye, Yingna Xu, Zhaotong Cong, Hao Li, Shi Lin, Dehua Yang, Ming-Wei Wang
Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-Gs in complex with γ-MSH and MC5R-Gs in the presence of α-MSH or a potent synthetic agonist PG-901...
July 31, 2023: Cell Discovery
https://read.qxmd.com/read/37425887/cell-autonomous-regulation-of-the-activation-of-agrp-neurons-by-the-melanocortin-3-receptor
#24
Yijun Gui, Naima S Dahir, Griffin Downing, Patrick Sweeney, Roger D Cone
The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on AgRP nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. Hence, animals lacking MC3R (MC3R KO) exhibit hypersensitivity to MC4R agonists. However, MC3R KO mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting and cold exposure, while exhibiting normal inhibition of AgRP neurons by sensory detection of food...
June 29, 2023: bioRxiv
https://read.qxmd.com/read/37398302/peripheral-mc1r-activation-modulates-immune-responses-and-is-neuroprotective-in-a-mouse-model-of-parkinson-s-disease
#25
Pranay Srivast, Shuhei Nishiyama, Sonia H Lin, Akriti Srivast, Chienwen Su, Weiyi Peng, Michael Levy, Michael Schwarzschild, Yuehang Xu, Xiqun Chen
Background : Melanocortin 1 receptor ( MC1R ) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable CNS permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells...
June 12, 2023: Research Square
https://read.qxmd.com/read/37393902/the-narrative-of-a-patient-with-leptin-receptor-deficiency-personalized-medicine-for-a-rare-genetic-obesity-disorder
#26
Mila S Welling, Lotte Kleinendorst, Mieke M van Haelst, Erica L T van den Akker
Leptin receptor deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life, however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had deep impact on the live of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl...
July 1, 2023: Obesity Facts
https://read.qxmd.com/read/37373293/the-parallel-structure-activity-relationship-screening-of-three-compounds-identifies-the-common-agonist-pharmacophore-of-pyrrolidine-bis-cyclic-guanidine-melanocortin-3-receptor-mc3r-small-molecule-ligands
#27
JOURNAL ARTICLE
Mark D Ericson, Katie T Freeman, Travis M LaVoi, Haley M Donow, Radleigh G Santos, Marc A Giulianotti, Clemencia Pinilla, Richard A Houghten, Carrie Haskell-Luevano
The melanocortin receptors are involved in numerous physiological pathways, including appetite, skin and hair pigmentation, and steroidogenesis. In particular, the melanocortin-3 receptor (MC3R) is involved in fat storage, food intake, and energy homeostasis. Small-molecule ligands developed for the MC3R may serve as therapeutic lead compounds for treating disease states of energy disequilibrium. Herein, three previously reported pyrrolidine bis-cyclic guanidine compounds with five sites for molecular diversity (R1-R5) were subjected to parallel structure-activity relationship studies to identify the common pharmacophore of this scaffold series required for full agonism at the MC3R...
June 14, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37369302/prefrontal-cortex-melanocortin-4-receptors-mc4r-mediate-food-intake-behavior-in-male-mice
#28
JOURNAL ARTICLE
Rachel A Ross, Angela Kim, Priyanka Das, Yan Li, Yong Kee Choi, Andy T Thompson, Ella Douglas, Siva Subramanian, Kat Ramos, Kathryn Callahan, Vadim Y Bolshakov, Kerry J Ressler
BACKGROUND: Melanocortin 4 receptor (MC4R) activity in the hypothalamus is crucial for regulation of metabolism and food intake. The peptide ligands for the MC4R are associated with feeding, energy expenditure, and also with complex behaviors that orchestrate energy intake and expenditure, but the downstream neuroanatomical and neurochemical targets associated with these behaviors are elusive. In addition to strong expression in the hypothalamus, the MC4R is highly expressed in the medial prefrontal cortex, a region involved in executive function and decision-making...
June 25, 2023: Physiology & Behavior
https://read.qxmd.com/read/37257508/evidence-for-a-feeding-related-association-between-melanocortin-in-the-nts-and-neuropeptide-y-in-the-pvn
#29
JOURNAL ARTICLE
E-M Kim, J G Quinn, R E Reid, E O'Hare
Melanocortin and neuropeptide-Y (NPY) are both involved in feeding and energy regulation, and they have opposite effects in the paraventricular nucleus of the hypothalamus (PVN). The present study examined an interaction between melanocortin in the nucleus of the solitary tract (NTS) and NPY in the PVN. Male Sprague-Dawley rats were implanted with cannulae in the injection sites of interest. In Experiment 1, subjects received either the melanocortin 3/4-receptor (MC3/4) antagonist SHU9119 (0, 10, 50 and 100 pmol/0...
May 29, 2023: Appetite
https://read.qxmd.com/read/37217094/the-multifunctional-human-ocular-melanocortin-system
#30
REVIEW
Chieh-Lin Stanley Wu, Adrian V Cioanca, Maria C Gelmi, Li Wen, Nick Di Girolamo, Ling Zhu, Riccardo Natoli, R Max Conway, Constantinos Petsoglou, Martine J Jager, Peter J McCluskey, Michele C Madigan
Immune privilege in the eye involves physical barriers, immune regulation and secreted proteins that together limit the damaging effects of intraocular immune responses and inflammation. The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) normally circulates in the aqueous humour of the anterior chamber and the vitreous fluid, secreted by iris and ciliary epithelium, and retinal pigment epithelium (RPE). α-MSH plays an important role in maintaining ocular immune privilege by helping the development of suppressor immune cells and by activating regulatory T-cells...
July 2023: Progress in Retinal and Eye Research
https://read.qxmd.com/read/37155917/correction-to-discovery-of-nanomolar-melanocortin-3-receptor-mc3r-selective-small-molecule-pyrrolidine-bis-cyclic-guanidine-agonist-compounds-via-a-high-throughput-unbiased-screening-campaign
#31
Skye R Doering, Katie Freeman, Ginamarie Debevec, Phaedra Geer, Radleigh G Santos, Travis M Lavoi, Marc A Giulianotti, Clemencia Pinilla, Jon R Appel, Richard A Houghten, Mark D Ericson, Carrie Haskell-Luevano
No abstract text is available yet for this article.
May 8, 2023: Journal of Medicinal Chemistry
https://read.qxmd.com/read/37133411/%C3%AE-and-%C3%AF-angle-constrains-at-the-c-terminus-trp-position-of-the-melanotropin-tetrapeptide-ac-his-d-phe-arg-trp-nh-2-lead-to-potent-and-selective-agonists-at-hmc1r-and-hmc4r
#32
JOURNAL ARTICLE
Yang Zhou, Saghar Mowlazadeh Haghighi, Jonathon R Sawyer, Victor J Hruby, Minying Cai
Melanocortin receptors (MCRs) are a family of G protein-coupled receptors that regulate important physiological functions. Yet, drug development targeting MCRs is hindered by potential side effects due to a lack of receptor subtype-selective ligands with bioavailability. Here, we report novel synthetic pathways to introduce Ψ and χ angle constraints at the C-terminus Trp position of the nonselective prototype tetrapeptide agonist Ac-His-d-Phe-Arg-Trp-NH2 . With these conformational constraints, peptide 1 (Ac-His-d-Phe-Arg-Aia) shows improved selectivity at hMC1R, with an EC50 of 11...
May 3, 2023: Journal of Medicinal Chemistry
https://read.qxmd.com/read/37126536/setmelanotide-optimization-through-fragment-growing-molecular-docking-in-silico-method-targeting-mc4-receptor
#33
JOURNAL ARTICLE
Xiaopu Jia, Shuai Fan, Weili Dong, Shaoyong Li, Yan Zhang, Ying Ma, Shuqing Wang
Obesity has emerged as a global issue, but with the complex structures of multiple related important targets and their agonists or antagonists determined, the mechanism of ligand-protein interaction may offer new chances for developing new generation agonists anti-obesity. Based on the molecule surface of the cryo-EM protein structure 7AUE, we tried to replace D-Ala3 with D-Met in setmelanotide as the linker site for fragment-growing with De novo evolution. The simulation results indicate that the derivatives could improve the binding abilities with the melanocortin 4 receptor and the selectivity over the melanocortin 1 receptor...
April 26, 2023: Journal of Biomolecular Structure & Dynamics
https://read.qxmd.com/read/37115703/mc1r-peptide-agonist-self-assembles-into-a-hydrogel-that-promotes-skin-pigmentation-for-treating-vitiligo
#34
JOURNAL ARTICLE
Ci Zhu, Tingting Li, Zhuole Wang, Zenghui Li, Jiaying Wei, Hong Han, Dan Yuan, Minying Cai, Junfeng Shi
Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. Herein, we report an MC1R peptide agonist that directly self-assembles into nanofibrils that form a hydrogel matrix under normal physiological conditions. This hydrogel exhibits higher stability than free peptides, sustained release, rapid recovery from shear-thinning, and resistance to enzymatic proteolysis...
May 9, 2023: ACS Nano
https://read.qxmd.com/read/37108092/stimulating-the-melanocortin-system-in-uveitis-and-diabetes-preserves-the-structure-and-anti-inflammatory-activity-of-the-retina
#35
JOURNAL ARTICLE
Tat Fong Ng, Andrew W Taylor
The endogenous neuropeptide α-Melanocyte Stimulating Hormone (α-MSH) is a potent suppressor of inflammation and has an essential role in maintaining the normal anti-inflammatory microenvironment of the retina. While the therapeutic use of α-MSH peptide in uveitis and diabetic retinopathy models has been demonstrated, its short half-life and instability limit its use as a therapeutic drug. A comparable analog, PL-8331, which has a stronger affinity to melanocortin receptors, longer half-life, and, so far, is functionally identical to α-MSH, has the potential to deliver melanocortin-based therapy...
April 8, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37085333/ramp-and-mrap-accessory-proteins-have-selective-effects-on-expression-and-signalling-of-the-cb1-cb2-gpr18-and-gpr55-cannabinoid-receptors
#36
JOURNAL ARTICLE
Nathaniel A K Glenn, David B Finlay, Emma R Carruthers, Kathleen G Mountjoy, Christopher S Walker, Natasha L Grimsey
BACKGROUND AND PURPOSE: Receptor activity-modifying proteins (RAMPs) and melanocortin receptor accessory proteins (MRAPs) modulate expression and signalling of calcitonin and melanocortin GPCRs. Interactions with other GPCRs have also been reported. Cannabinoid receptors (CBRs) CB1 and CB2 , and putative CBRs GPR18 and GPR55, exhibit substantial intracellular expression and there are discrepancies in ligand responsiveness between studies. We investigated whether interactions with RAMPs or MRAPs could explain these phenomena...
April 21, 2023: British Journal of Pharmacology
https://read.qxmd.com/read/37078227/absorption-metabolism-and-excretion-of-14-c-dersimelagon-an-investigational-oral-selective-melanocortin-1-receptor-agonist-in-preclinical-species-and-healthy-volunteers
#37
JOURNAL ARTICLE
Minoru Tsuda, Kei Ogawa, Tadashi Endou, Takahiro Goto, Yuko Ogasawara, Akihito Ogasawara
Dersimelagon (formerly MT-7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [14 C]dersimelagon in healthy adult volunteers (N = 6) who participated in phase 1, single-center, open-label, mass balance study (NCT03503266), and in preclinical animal models are presented...
June 2023: Pharmacology Research & Perspectives
https://read.qxmd.com/read/37047638/the-melanocortin-system-a-promising-target-for-the-development-of-new-antidepressant-drugs
#38
REVIEW
Dmitrii D Markov, Oleg V Dolotov, Igor A Grivennikov
Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression...
April 3, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/37043653/dersimelagon-in-erythropoietic-protoporphyrias
#39
RANDOMIZED CONTROLLED TRIAL
Manisha Balwani, Herbert L Bonkovsky, Cynthia Levy, Karl E Anderson, D Montgomery Bissell, Charles Parker, Fumihiro Takahashi, Robert J Desnick, Kirstine Belongie
BACKGROUND: Erythropoietic protoporphyria and X-linked protoporphyria are inborn errors of heme biosynthesis that cause elevated circulating levels of metal-free protoporphyrin and phototoxicity. Both disorders are characterized by excruciating phototoxic attacks after exposure to visible light. Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin. METHODS: We conducted a randomized, placebo-controlled, phase 2 trial to investigate the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria...
April 13, 2023: New England Journal of Medicine
https://read.qxmd.com/read/37013719/an-evaluation-of-setmelanotide-injection-for-chronic-weight-management-in-adult-and-pediatric-patients-with-obesity-due-to-bardet-biedl-syndrome
#40
JOURNAL ARTICLE
Julia Lazareva, Sheila M Brady, Jack A Yanovski
INTRODUCTION: Bardet-Biedl Syndrome (BBS) is a rare, multisystemic ciliopathy with an incidence of obesity of 89%. Mutations in genes encoding BBS proteins are linked to reduced leptin sensitivity of hypothalamic POMC neurons and reduced activation of the melanocortin-4 receptor (MC4R) pathway due to deficient α-MSH production by hypothalamic POMC neurons. The MC4R pathway is involved in controlling body weight and energy metabolism, and its disruption is linked to hyperphagia and obesity...
April 4, 2023: Expert Opinion on Pharmacotherapy
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