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Pharmaceuticals
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Adenosine Receptors as Attractive Targets in Human Diseases
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Adenosine Receptors as Attractive Targets in Human Diseases

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 26486

Special Issue Editors

Prof. Dr. Vittoria Colotta

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Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Daniela Catarzi

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals
Dr. Flavia Varano

E-Mail Website
Guest Editor
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, FI, Italy
Interests: medicinal chemistry; rational drug design; heterocyclic compounds; structure–activity relationships; adenosine receptor ligands; carbonic anhydrase inhibitors; protein kinase CK1 and CK2 inhibitors; ecto-5'-nucleotidase (CD73) inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Adenosine is a ubiquitous neuromodulator, both in the central and peripheral nervous systems, and is also present in almost all organs and tissues. It activates G-protein coupled receptors, classified as A1, A2A, A2B and A3 adenosine receptor (AR) subtypes, which have different tissue/organ distribution and effector couplings. Thus, adenosine modulates a wide variety of physiological processes, such as neuronal and cardiovascular activities, immune system functions and cellular metabolism, and it is also implicated in different pathological conditions. Although AR roles are still far from being completely understood, targeting ARs has been proven to be a valid mean for therapeutic and diagnostic intervention in several diseases, thus prompting scientists to search for new molecules able to modulate, directly or indirectly, AR functions. This Special Issue is aimed at providing the reader with recent advances in the field of ARs as target in human diseases.

Authors are invited to submit original articles dealing with their research in this area of investigation. The proposed topics include, but are not limited to, new AR ligands, AR allosteric modulators or enzyme modulators, designed as chemical probe for the study of adenosine pharmacological role and to highlight the AR-mediated therapeutic effects. Review articles summarizing the current knowledge on adenosine receptors and their ligands will be also of interest.

Prof. Vittoria Colotta
Prof. Daniela Catarzi
Dr. Flavia Varano
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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • G protein-coupled receptors
  • adenosine receptors
  • adenosine receptor ligands
  • allosteric modulators
  • rational design
  • multitarget-directed drugs
  • computational studies
  • molecular docking
  • therapeutics

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 199 KiB  
Editorial
Special Issue “Adenosine Receptors as Attractive Targets in Human Diseases”
by Daniela Catarzi, Flavia Varano and Vittoria Colotta
Pharmaceuticals 2021, 14(2), 140; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020140 - 10 Feb 2021
Viewed by 1211
Abstract
The idea of promoting this Special Issue arises from the desire to witness the multidisciplinary efforts that are currently in progress to provide new insights into the pathophysiological role of adenosine [...] Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)

Research

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21 pages, 5200 KiB  
Article
Adenosine Receptor Agonists Increase the Inhibition of Platelet Function by P2Y12 Antagonists in a cAMP- and Calcium-Dependent Manner
by Nina Wolska, Hassan Kassassir, Boguslawa Luzak, Cezary Watala and Marcin Rozalski
Pharmaceuticals 2020, 13(8), 177; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080177 - 31 Jul 2020
Cited by 5 | Viewed by 4759
Abstract
We have shown previously that platelet activity can be lowered through the simultaneous inhibition of P2Y12 receptor and activation of adenosine receptors (AR). This work explores this concept by testing the antiplatelet potential of nine AR agonists in combination with P2Y12 [...] Read more.
We have shown previously that platelet activity can be lowered through the simultaneous inhibition of P2Y12 receptor and activation of adenosine receptors (AR). This work explores this concept by testing the antiplatelet potential of nine AR agonists in combination with P2Y12 receptor antagonists—cangrelor and prasugrel metabolite. A panel of in vitro methods was used to assess platelet viability, P-selectin expression, GPIIb-IIIa activation, fibrinogen binding, calcium ion mobilization, VASP-P level, and cAMP formation, utilizing whole blood or isolated platelets from healthy volunteers. The AR agonists demonstrated anti-platelet effects, but stimulated signaling pathways to varying degrees. AR agonists and P2Y12 antagonists reduced expression of both P-selectin and the activated form of GPIIb-IIIa on platelets; however, the combined systems (AR agonist + P2Y12 antagonist) demonstrated stronger effects. The antiplatelet effects of AR when combined with P2Y12 were more pronounced with regard to exogenous fibrinogen binding and calcium mobilization. The cAMP levels in both resting and ADPactivated platelets were increased by AR agonist treatment, and more so when combined with P2Y12 inhibitor. In conclusion, as AR agonists are fast-acting compounds, the methods detecting early activation events are more suitable for assessing their antiplatelet action. The exogenous fibrinogen binding, calcium mobilisation and cAMP level turned out to be sensitive markers for detecting the inhibition caused by AR agonists alone or in combination with P2Y12 receptor antagonists. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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19 pages, 10462 KiB  
Article
Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists
by Flavia Varano, Daniela Catarzi, Erica Vigiani, Fabrizio Vincenzi, Silvia Pasquini, Katia Varani and Vittoria Colotta
Pharmaceuticals 2020, 13(8), 161; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080161 - 24 Jul 2020
Cited by 11 | Viewed by 2767
Abstract
The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor [...] Read more.
The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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22 pages, 9698 KiB  
Article
Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists
by Daniela Catarzi, Flavia Varano, Katia Varani, Fabrizio Vincenzi, Silvia Pasquini, Diego Dal Ben, Rosaria Volpini and Vittoria Colotta
Pharmaceuticals 2019, 12(4), 159; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12040159 - 22 Oct 2019
Cited by 9 | Viewed by 4418
Abstract
The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not [...] Read more.
The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure–activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1H-imidazol-2-yl group at R2 position as an important feature for producing potent AR agonists. Moreover, the nature of the R1 substituent highly affects not only affinity/activity at the hA1 and hA2B ARs but also selectivity versus the other subtypes. Potent hA1 and hA2B AR ligands were developed, and among them, the 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile (3) is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA2A and hA3 ARs. This combined hA1/hA2B partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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Review

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22 pages, 612 KiB  
Review
Adenosine Signaling in Autoimmune Disorders
by Giulia Magni and Stefania Ceruti
Pharmaceuticals 2020, 13(9), 260; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13090260 - 22 Sep 2020
Cited by 20 | Viewed by 3400
Abstract
The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and [...] Read more.
The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any “danger” condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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21 pages, 2622 KiB  
Review
Chemical Probes for the Adenosine Receptors
by Stephanie Federico, Lucia Lassiani and Giampiero Spalluto
Pharmaceuticals 2019, 12(4), 168; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12040168 - 12 Nov 2019
Cited by 9 | Viewed by 4161
Abstract
Research on the adenosine receptors has been supported by the continuous discovery of new chemical probes characterized by more and more affinity and selectivity for the single adenosine receptor subtypes (A1, A2A, A2B and A3 adenosine receptors). [...] Read more.
Research on the adenosine receptors has been supported by the continuous discovery of new chemical probes characterized by more and more affinity and selectivity for the single adenosine receptor subtypes (A1, A2A, A2B and A3 adenosine receptors). Furthermore, the development of new techniques for the detection of G protein-coupled receptors (GPCR) requires new specific probes. In fact, if in the past radioligands were the most important GPCR probes for detection, compound screening and diagnostic purposes, nowadays, increasing importance is given to fluorescent and covalent ligands. In fact, advances in techniques such as fluorescence resonance energy transfer (FRET) and fluorescent polarization, as well as new applications in flow cytometry and different fluorescence-based microscopic techniques, are at the origin of the extensive research of new fluorescent ligands for these receptors. The resurgence of covalent ligands is due in part to a change in the common thinking in the medicinal chemistry community that a covalent drug is necessarily more toxic than a reversible one, and in part to the useful application of covalent ligands in GPCR structural biology. In this review, an updated collection of available chemical probes targeting adenosine receptors is reported. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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22 pages, 2943 KiB  
Review
Non-Nucleoside Agonists of the Adenosine Receptors: An Overview
by Diego Dal Ben, Catia Lambertucci, Michela Buccioni, Aleix Martí Navia, Gabriella Marucci, Andrea Spinaci and Rosaria Volpini
Pharmaceuticals 2019, 12(4), 150; https://0-doi-org.brum.beds.ac.uk/10.3390/ph12040150 - 08 Oct 2019
Cited by 12 | Viewed by 4958
Abstract
Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of [...] Read more.
Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of compounds selective for a specific AR subtype (i.e., A2BAR) and a generally long and complex synthetic route for largely substituted nucleosides are the main drawbacks of this category of molecules. Non-nucleoside agonists represent an alternative set of compounds able to stimulate the AR function and based on simplified structures. This review provides an updated overview on the structural classes of non-nucleoside AR agonists and their biological activities, with emphasis on the main derivatives reported in the literature. A focus is also given to the synthetic routes employed to develop these derivatives and on molecular modeling studies simulating their interaction with ARs. Full article
(This article belongs to the Special Issue Adenosine Receptors as Attractive Targets in Human Diseases)
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