ArticleEuropean journal of pharmacology2011
Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay.
Article in European journal of pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 41 citations in OpenAlex.
- Melanocortin-4 receptor complexity in energy homeostasis,obesity and drug development strategies.Diabetes, obesity & metabolism · 2022Review
- In vivo Screening of Natural Products Against Angiogenesis and Mechanisms of Anti-Angiogenic Activity of Deoxysappanone B 7,4'-Dimethyl Ether.Drug design, development and therapy · 2020Article
- Identification of mundoserone by zebrafishExperimental and therapeutic medicine · 2018Article
- Melanocortins, Melanocortin Receptors and Multiple Sclerosis.Brain sciences · 2017Review
- Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.Cellular and molecular life sciences : CMLS · 2017Article
- A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo.Drug metabolism and disposition: the biological fate of chemicals · 2015Article
- Article
- Osthole: A Review on Its Bioactivities, Pharmacological Properties, and Potential as Alternative Medicine.Evidence-based complementary and alternative medicine : eCAM · 2015Review
- MC4R expression in pedunculopontine nucleus involved in the modulation of midbrain dopamine system.International journal of clinical and experimental pathology · 2015Article
- Genetically-encoded tools for cAMP probing and modulation in living systems.Frontiers in pharmacology · 2015Review
- A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors.Journal of biomolecular screening · 2014Article
- Development of an assay for high-throughput energy expenditure monitoring in the zebrafish.Zebrafish · 2013Article
- SET protein interacts with intracellular domains of the gonadotropin-releasing hormone receptor and differentially regulates receptor signaling to cAMP and calcium in gonadotrope cells.The Journal of biological chemistry · 2013Article
- Melanocortin-3 receptors and metabolic homeostasis.Progress in molecular biology and translational science · 2013Review
- Manipulation of very few receptor discriminator residues greatly enhances receptor specificity of non-visual arrestins.The Journal of biological chemistry · 2012Article
- Probing heterotrimeric G protein activation: applications to biased ligands.Current pharmaceutical design · 2012Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The melanocortin MC(4) receptor is a potential target for the development of drugs for both obesity and cachexia. Melanocortin MC(4) receptor ligands known thus far are orthosteric agonists or antagonists, however the agonists, in particular, have generally exhibited unwanted side effects. For some receptors, allosteric modulators are expected to reduce side-effect profiles. To identify allosteric modulators of the melanocortin MC(4) receptor, we created HEK293 cell lines coexpressing the human melanocortin MC(4) receptor and a modified luciferase-based cAMP sensor. Monitoring luminescence as a readout of real-time intracellular cAMP concentration, we demonstrate that this cell line is able to report melanocortin agonist responses, as well as inverse agonist response to the physiological AgRP peptide. Based on the MC4R-GLO cell line, we developed an assay that was shown to meet HTS standards (Z'=0.50). A pilot screen run on the Microsource Spectrum compound library (n=2000) successfully identified 62 positive modulators. This screen identified predicted families of compounds: β(2)AR agonists - the β(2)AR being endogenously expressed in HEK293 cells, an adenylyl cyclase activator and finally a distribution of phosphodiesterase (PDE) inhibitors well characterized or recently identified. In this last category, we identified a structural family of coumarin-derived compounds (imperatorin, osthol and prenyletin), along with deracoxib, a drug in veterinary use for its COX2 inhibitory properties. This latter finding unveiled a new off-target mechanism of action for deracoxib as a PDE inhibitor. Overall, these data are the first report of a HTS for allosteric modulators for a Gs protein coupled receptor.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.