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Cells
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Adenosine and Purinergic Receptors: Regulation and Essential Role in Human...
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Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 March 2025) | Viewed by 4382

Special Issue Editors

Dr. Veronica Salmaso

E-Mail Website
Guest Editor
Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy
Interests: molecular modeling; drug design; purinergic receptors
Dr. Stephanie Federico

E-Mail Website
Guest Editor
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy
Interests: synthesis of heterocycles; structure–activity relationship; adenosine receptors
Prof. Dr. Stefano Moro

E-Mail Website
Guest Editor
Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy
Interests: molecular modeling; drug design; purinergic receptors

Special Issue Information

Dear Colleagues,

The purinergic signaling system comprises both adenosine receptors (ARs) and purinergic receptors (P2Rs), where adenosine and nucleotides act as extracellular messengers, respectively.

In particular, adenosine exerts its function through the activation of four AR subtypes, A1, A2A, A2B, and A3, which are G protein-coupled receptors, while P2Rs comprise both ionotropic receptors (P2X1-7R) and metabotropic receptors (P2Y1,2,4,6,11-14R). The signaling pathways activated by ligand–receptor interaction are cross-linked with other transmitter networks to regulate numerous key physiological processes like proliferation, differentiation, and apoptosis. Thus, the deregulation of the system establishes pathological conditions that include, but are not limited to, inflammation, cancer, and neurodegeneration. Few adenosinergic and purinergic drugs have been approved to date. Great efforts are still focused on the research and development of ligands, with emerging interest in the field of allosteric modulation, biased agonism, and bitopic ligands. On the other hand, even more efforts are ongoing in understanding the pathophysiological implications of the different receptors in order to validate them as targets in specific diseases.

With this Special Issue, we aim to shed light on the pharmacology of AR and P2R, as well as present the advancements in the development of ligands towards them. We look forward to receiving your contributions.

Dr. Veronica Salmaso
Dr. Stephanie Federico
Prof. Dr. Stefano Moro
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • adenosine receptors
  • adenosine
  • purinergic signaling
  • P2 receptors
  • GPCRs
  • neurodegeneration
  • cancer
  • pain
  • inflammation
  • ischemia

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Published Papers (3 papers)

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15 pages, 1308 KiB  
Article
A2A Adenosine Receptor Antagonists and Their Efficacy in Rat Models of Parkinson’s Disease
by Andrea Spinaci, Michela Buccioni, Diego Dal Ben, Beatrice Francucci, Karl-Norbert Klotz, Gabriella Marucci, Nicola Simola, Micaela Morelli, Annalisa Pinna, Rosaria Volpini and Catia Lambertucci
Cells 2025, 14(5), 338; https://doi.org/10.3390/cells14050338 - 26 Feb 2025
Viewed by 735
Abstract
Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated [...] Read more.
Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A2A adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A2A adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A2A adenosine receptor-binding affinities in the low nanomolar range and 1, 4, and 5 exhibited good potency in the functional assays. Hence, they were evaluated in in vivo rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, 4, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (4) as an A2A adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease. Full article
(This article belongs to the Special Issue Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease)
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14 pages, 2426 KiB  
Article
Mechanistic Insights into the Adenosine A1 Receptor’s Positive Allosteric Modulation for Non-Opioid Analgesics
by Tal Weizmann, Abigail Pearce, Peter Griffin, Achille Schild, Maren Flaßhoff, Philipp Grossenbacher, Martin Lochner, Christopher A. Reynolds, Graham Ladds and Giuseppe Deganutti
Cells 2024, 13(24), 2121; https://doi.org/10.3390/cells13242121 - 21 Dec 2024
Cited by 1 | Viewed by 1698
Abstract
The adenosine A1 receptor (A1R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the [...] Read more.
The adenosine A1 receptor (A1R) is a promising target for pain treatment. However, the development of therapeutic agonists is hampered by adverse effects, mainly including sedation, bradycardia, hypotension, or respiratory depression. Recently discovered molecules able to overcome this impediment are the positive allosteric modulator MIPS521 and the A1R-selective agonist BnOCPA, which are both potent and powerful analgesics with fewer side effects. While BnOCPA directly activates the A1R from the canonical orthosteric site, MIPS521 binds to an allosteric site, acting in concert with orthosteric adenosine and tuning its pharmacology. Given their overlapping profile in pain models but distinct mechanisms of action, we combined pharmacology and microsecond molecular dynamics simulations to address MIPS521 and BnOCPA activity and their reciprocal influence when bound to the A1R. We show that MIPS521 changes adenosine and BnOCPA G protein selectivity in opposite ways and propose a structural model where TM7 dynamics are differently affected and involved in the G protein preferences of adenosine and BnOCPA. Full article
(This article belongs to the Special Issue Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease)
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14 pages, 1664 KiB  
Article
Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists
by Paola Oliva, Asmita Pramanik, Young-Hwan Jung, Sarah A. Lewicki, Jamie M. Mwendwa, Jong Hwan Park and Kenneth A. Jacobson
Cells 2024, 13(16), 1366; https://doi.org/10.3390/cells13161366 - 16 Aug 2024
Viewed by 1361
Abstract
The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have [...] Read more.
The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, although high affinity is lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced affinity in the antagonism of UDP-induced Ca2+ mobilization in human (h) P2Y6R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC50 of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative 30, and 132-fold selective compared to the P2Y14R. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2Y6R affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives 20, 24, 26, 30, 31, and 37, which showed multiple interactions, particularly at the biogenic amine receptors. The more potent analogues may be suitable for evaluation in inflammation and cancer models, which will be performed in future studies. Full article
(This article belongs to the Special Issue Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease)
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