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Cited by 29Adenosine and Purinergic SignalingBiochemical and Molecular ResearchReceptor Mechanisms and Signaling

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

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Pasquini, Silvia, Contri, Chiara, Cappello, Martina, Borea, Pier Andrea, Varani, Katia, Vincenzi, Fabrizio·2022·Frontiers in Pharmacology
DOI 10.3389/fphar.2022.1030895PMC PMC9581118
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Abstract

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 A 1 and various A 3 AR 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 A 2A and A 2B AR 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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  • A2A receptor activation by PDRN modulates anti-inflammatory responses, angiogenesis, and vasodilation.

    “This effect modulates key physiological processes such as anti-inflammatory responses, angiogenesis, and vasodilation, as illustrated in Figure 2 (left panel) [52,66,67,68].”

    From Comparison of Polynucleotide and Polydeoxyribonucleotide in Dermatology: Molecular Mechanisms and Clinical Perspectives (2025) · cites this paper as [67]

    The “A2AAR allosteric modulators” section (page unavailable) links A2A receptor activation to anti-inflammatory effects and says A2A agonists can have a significant hypotensive effect. It does not identify PDRN as the activator or discuss angiogenesis or vasodilation, so it supports only part of the attributed claim. (LLM, conf=0.85)

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Cited by

Sorted by citations

Authors
Pasquini, S., Contri, C., Cappello, M., Borea, P. A., Varani, K., & Vincenzi, F.
Affiliations
University of Ferrara (IT)
Corresponding author
Varani, Katia
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2022-10-05
Volume
13
Pages
1030895-1030895
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2022.1030895
PMC
PMC9581118
OpenAlex
W4301430540
Cited by
29
References
0
Citations by year
2026: 5 · 2025: 10 · 2024: 6 · 2023: 8
FWCI
1.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
adenosine receptors, allosteric modulators, adenosine A1 receptor, A3 adenosine receptor, adenosine A2A receptor, adenosine A2B receptor, orthosteric ligands, drug development, therapeutic target, inflammatory diseases, central nervous system disorders, cardiovascular disease, metabolic disorders

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