Novel positive allosteric modulators of A<sub>2B</sub> adenosine receptor acting as bone mineralisation promoters

Barresi, Elisabetta; Giacomelli, Chiara; Marchetti, Laura; Baglini, Emma; Salerno, Silvia; Greco, Giovanni; Settimo, Federico Da; Martini, Claudia; Trincavelli, Maria Letizia; Taliani, Sabrina

doi:10.1080/14756366.2020.1862103

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…Positive allosteric modulators (PAMs) increasing the potency or efficacy of agonists, and negative allosteric modulators (NAMs) acting as noncompetitive antagonists, have been reported for various AR subtypes, especially for the A 1 AR. The AR-PAMs that have been developed so far display only moderate potency or selectivity, and their usefulness is still unclear ( Fredholm et al, 2011 ; Göblyös and IJzerman, 2011 ; Jacobson et al, 2011 ; Müller et al, 2012 ; Nguyen et al, 2016 ; Barresi et al, 2021 ). Interestingly, in a recent cryo-EM structure of the A 1 AR, a PAM (MIPS521) was found to be localized in an extrahelical domain ( Draper-Joyce et al, 2021 ).…”

Section: Receptor Ligands (For Structures See Figs 1 ...mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

et al. 2022

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Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. Significance Statement Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists (“biased” or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A 2A - and A 2B AR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A 2A AR antagonist (istradefylline) has been approved as an anti-Parkinson agent.

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Section: Receptor Ligands (For Structures See Figs 1 ...mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

et al. 2022

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“…Barresi et al investigated combinations of an orthosteric A2b receptor activator with several allosteric A2b receptor activators on human BMMSCs osteogenic differentiation. Results of the assay revealed that combination of the two types of agonists improved tissue mineralization [ 72 ].…”

Section: Small Moleculesmentioning

confidence: 99%

Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways

et al. 2022

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Bone-related diseases are major contributors to morbidity and mortality in elderly people and the current treatments result in insufficient healing and several complications. One of the promising areas of research for healing bone fractures and skeletal defects is regenerative medicine using stem cells. Differentiating stem cells using agents that shift cell development towards the preferred lineage requires activation of certain intracellular signaling pathways, many of which are known to induce osteogenesis during embryological stages. Imitating embryological bone formation through activation of these signaling pathways has been the focus of many osteogenic studies. Activation of osteogenic signaling can be done by using small molecules. Several of these agents, e.g., statins, metformin, adenosine, and dexamethasone have other clinical uses but have also shown osteogenic capacities. On the other hand, some other molecules such as T63 and tetrahydroquinolines are not as well recognized in the clinic. Osteogenic small molecules exert their effects through the activation of signaling pathways known to be related to osteogenesis. These pathways include more well-known pathways including BMP/Smad, Wnt, and Hedgehog as well as ancillary pathways including estrogen signaling and neuropeptide signaling. In this paper, we review the recent data on small molecule-mediated osteogenic differentiation, possible adjunctive agents with these molecules, and the signaling pathways through which each small molecule exerts its effects. Graphical Abstract

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“…The four adenosine receptor subtypes can be broadly classified into two classes. Baressi et al described a type of A 2B R allosteric modulators with good selectivity over the other subtypes, these compounds contain a 1,3-substituted indole unit ( Barresi et al, 2021a ; Barresi et al, 2021b ). Lu et al established a fragment screening method using mass spectrometry to screen GPCR ligands, identifying an A 2A R NAM.…”

Section: Allosteric Modulators In the Class A Gpcr Fieldmentioning

confidence: 99%

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

2022

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G-protein coupled receptors (GPCRs) are considered important therapeutic targets due to their pathophysiological significance and pharmacological relevance. Class A receptors represent the largest group of GPCRs that gives the highest number of validated drug targets. Endogenous ligands bind to the orthosteric binding pocket (OBP) embedded in the intrahelical space of the receptor. During the last 10 years, however, it has been turned out that in many receptors there is secondary binding pocket (SBP) located in the extracellular vestibule that is much less conserved. In some cases, it serves as a stable allosteric site harbouring allosteric ligands that modulate the pharmacology of orthosteric binders. In other cases it is used by bitopic compounds occupying both the OBP and SBP. In these terms, SBP binding moieties might influence the pharmacology of the bitopic ligands. Together with others, our research group showed that SBP binders contribute significantly to the affinity, selectivity, functional activity, functional selectivity and binding kinetics of bitopic ligands. Based on these observations we developed a structure-based protocol for designing bitopic compounds with desired pharmacological profile.

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Novel positive allosteric modulators of A_2B adenosine receptor acting as bone mineralisation promoters

Cited by 13 publications

References 33 publications

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

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Novel positive allosteric modulators of A2B adenosine receptor acting as bone mineralisation promoters

Cited by 13 publications

References 33 publications

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

Contact Info

Product

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Novel positive allosteric modulators of A_2B adenosine receptor acting as bone mineralisation promoters