Allosterism vs. Orthosterism: Recent Findings and Future Perspectives on A2B AR Physio-Pathological Implications

Barresi, Elisabetta; Martini, Claudia; Settimo, Federico Da; Greco, Giovanni; Taliani, Sabrina; Giacomelli, Chiara; Trincavelli, Maria Letizia

doi:10.3389/fphar.2021.652121

Cited by 6 publications

(4 citation statements)

References 57 publications

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“…These findings confirm that EA 575 ® is able to inhibit the A 2B AR signalling pathway and that this can be explained by an indirect mechanism of action. Since adenosine receptors are ubiquitously expressed in humans, this could be advantageous over orthosteric antagonism in terms of adverse effects [56]. To our knowledge, the present study is the first to show the influence of an ivy extract on adenosine receptor A 2B .…”

Section: Discussionmentioning

confidence: 64%

Ivy Leaf Dry Extract EA 575® Has an Inhibitory Effect on the Signalling Cascade of Adenosine Receptor A2B

Meurer

Häberlein

Franken

2023

IJMS

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Ivy leaf dry extract EA 575® is used to improve complaints of chronic inflammatory bronchial diseases and acute inflammation of the respiratory tract accompanied by coughing. Its mechanism of action has so far been explained by influencing β2-adrenergic signal transduction. In the present study, we investigated a possible influence on adenosine receptor A2B (A2BAR) signalling, as it has been described to play a significant and detrimental role in chronic inflammatory airway diseases. The influence of EA 575® on A2BAR signalling was assessed with measurements of dynamic mass redistribution. Subsequently, the effects on A2BAR-mediated second messenger cAMP levels, β-arrestin 2 recruitment, and cAMP response element (CRE) activation were examined using luciferase-based HEK293 reporter cell lines. Lastly, the impact on A2BAR-mediated IL-6 release in Calu-3 epithelial lung cells was investigated via the Lumit™ Immunoassay. Additionally, the adenosine receptor subtype mediating these effects was specified, and A2BAR was found to be responsible. The present study demonstrates an inhibitory influence of EA 575® on A2BAR-mediated general cellular response, cAMP levels, β-arrestin 2 recruitment, CRE activation, and IL-6 release. Since these EA 575®-mediated effects occur within a time frame of several hours of incubation, its mode of action can be described as indirect. The present data are the first to describe an inhibitory effect of EA 575® on A2BAR signalling. This may offer an explanation for the beneficial clinical effects of the extract in adjuvant asthma therapy.

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Section: Discussionmentioning

confidence: 64%

Ivy Leaf Dry Extract EA 575® Has an Inhibitory Effect on the Signalling Cascade of Adenosine Receptor A2B

Meurer

Häberlein

Franken

2023

IJMS

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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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“…More recently, a series of novel derivatives chemically related to those previously synthesized has been reported. One of these compounds, a benzofurane derivative that was confirmed to behave as A 2B AR PAM, stimulated matrix mineralization in MSC, making it a lead structure for the synthesis of new compounds with anti-osteoporosis properties ( Barresi et al, 2021a ; 2021b ).…”

Section: Allosteric Modulation Of Arsmentioning

confidence: 99%

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

et al. 2022

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Adenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A1 and various A3AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A2A and A2BAR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands.

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Allosterism vs. Orthosterism: Recent Findings and Future Perspectives on A2B AR Physio-Pathological Implications

Cited by 6 publications

References 57 publications

Ivy Leaf Dry Extract EA 575® Has an Inhibitory Effect on the Signalling Cascade of Adenosine Receptor A2B

Ivy Leaf Dry Extract EA 575® Has an Inhibitory Effect on the Signalling Cascade of Adenosine Receptor A2B

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

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

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