ArticleBritish journal of pharmacology2015
Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 84 citations in OpenAlex.
- Calcimimetics and CaSR signaling in CKD-MBD: bone-immune-vascular crosstalk and therapeutic potential.Frontiers in immunology · 2026Review
- Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor.Molecular pharmacology · 2025Article
- Sustainable Synthesis of Medicinally Important Heterocycles.Mini reviews in medicinal chemistry · 2025Review
- Evolutionary history of calcium-sensing receptors unveils hyper/hypocalcemia-causing mutations.PLoS computational biology · 2024Article
- Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.Science (New York, N.Y.) · 2024Article
- Calcium-sensing receptor regulates Kv7 channels via GBritish journal of pharmacology · 2024Article
- Structure, function and drug discovery of GPCR signaling.Molecular biomedicine · 2023Review
- Location bias: A "Hidden Variable" in GPCR pharmacology.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Review
- Design, synthesis and evaluation of novel 2-phenyl-3-(1H-pyrazol-4-yl)pyridine positive allosteric modulators for the MEuropean journal of medicinal chemistry · 2023Article
- Allosteric modulation of G protein-coupled receptor signaling.Frontiers in endocrinology · 2023Review
- Taste Cells of the Type III Employ CASR to Maintain Steady Serotonin Exocytosis at Variable CaCells · 2022Article
- AC-265347 Inhibits Neuroblastoma Tumor Growth by Induction of Differentiation without Causing Hypocalcemia.International journal of molecular sciences · 2022Article
- Therapeutic Opportunities of Targeting Allosteric Binding Sites on the Calcium-Sensing Receptor.ACS pharmacology & translational science · 2021Review
- Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery.Trends in pharmacological sciences · 2021Review
- International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.Pharmacological reviews · 2020Review
- Negative allosteric modulators of the human calcium-sensing receptor bind to overlapping and distinct sites within the 7-transmembrane domain.British journal of pharmacology · 2020Article
- New Advances in Targeting the Resolution of Inflammation: Implications for Specialized Pro-Resolving Mediator GPCR Drug Discovery.ACS pharmacology & translational science · 2020Review
- Factors inhibiting intestinal calcium absorption: hormones and luminal factors that prevent excessive calcium uptake.The journal of physiological sciences : JPS · 2019Review
- KACS omega · 2019Article
- Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.Neuropharmacology · 2019Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeClinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. EXPERIMENTAL APPROACH: We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. KEY
resultsPhenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). CONCLUSIONS AND IMPLICATIONS: The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.
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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.