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Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 16884

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Prof. Dr. Katia Varani

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Department of Translational Medicine, University of Ferrara, Ferrara, Italy
Interests: purinergic receptors; cell signaling transduction; chronic inflammatory diseases; neurodegenerative disorders; drug discovery
Special Issues, Collections and Topics in MDPI journals

Dr. Stefania Gessi

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Department of Translational Medicine, University of Ferrara, Ferrara, Italy
Interests: adenosine receptors; drug–receptor interactions; intracellular signaling; neuroinflammation; drug discovery
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Dr. Stefania Merighi

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Department of Translational Medicine, University of Ferrara, Ferrara, Italy
Interests: purinergic receptors; receptor signaling pathways; neurodegeneration; drug discovery
Special Issues, Collections and Topics in MDPI journals

Dr. Fabrizio Vincenzi

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Department of Translational Medicine, University of Ferrara, Ferrara, Italy
Interests: adenosine; cell signaling; drug discovery; allosteric modulation

Special Issue Information

Dear Colleagues,

Biomolecules invites submissions for a Special Issue in honor of Professor Pier Andrea Borea in recognition for his remarkable pharmacological contribution in the field of purinergic receptors.

Professor Pier Andrea Borea devoted most of his scientific research to the study of adenosine receptors starting from the early 1990s, when the significance of the purinergic system in the control of numerous human body processes was just beginning to be recognized. Since then, intense scientific work has been conducted to demonstrate the role of purines as important extracellular messengers, through their interaction with GPCRs and channel receptors, both markers and drug targets for the diagnosis and treatment of a wide range of diseases. It is clear today that the search for molecules that can alter the activity of purinergic receptors might lead to the development of novel medications for illnesses of the central and peripheral nervous systems, as well as the immune system, spanning from inflammatory disorders to ischemia, epilepsy, neuropathic pain, and cancer. These years of research have resulted in the development of a large number of ligands designed to interact with purinergic receptors, some of which have found utility in both diagnostic and therapeutic applications.

In this Special Issue of Biomolecules we invite your contributions, in the form of original research articles or reviews, on all aspects related to recent advances in the fields of purinergic receptors in health and disease, including cardiovascular, neurological, cancer, inflammatory, and immunological disorders. This Special Issue is dedicated to Professor Pier Andrea Borea for his invaluable contribution to this field.

We look forward to receiving your contributions.

Prof. Dr. Katia Varani
Dr. Stefania Gessi
Dr. Stefania Merighi
Dr. Fabrizio Vincenzi
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. Biomolecules 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 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 and ATP
P1 and P2 receptors
drug discovery
CNS diseases
immune and inflammatory diseases
cardiovascular pathologies
cancer
biomarkers

Published Papers (10 papers)

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Research

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11 pages, 1841 KiB

Open AccessArticle

Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors

by Veronica Salmaso, Margherita Persico, Tatiana Da Ros, Giampiero Spalluto, Sonja Kachler, Karl-Norbert Klotz, Stefano Moro and Stephanie Federico

Biomolecules 2023, 13(11), 1610; https://doi.org/10.3390/biom13111610 - 03 Nov 2023

Viewed by 744

Abstract

Adenosine receptors are largely distributed in our organism and are promising therapeutic targets for the treatment of many pathologies. In this perspective, investigating the structural features of the ligands leading to affinity and/or selectivity is of great interest. In this work, we have focused on a small series of pyrazolo-triazolo-pyrimidine antagonists substituted in positions 2, 5, and N8, where bulky acyl moieties at the N5 position and small alkyl groups at the N8 position are associated with affinity and selectivity at the A₃ adenosine receptor even if a good affinity toward the A_2B adenosine receptor has also been observed. Conversely, a free amino function at the 5 position induces high affinity at the A_2A and A₁ receptors with selectivity vs. the A₃ subtype. A molecular modeling study suggests that differences in affinity toward A₁, A_2A, and A₃ receptors could be ascribed to two residues: one in the EL2, E168 in human A_2A/E172 in human A₁, that is occupied by the hydrophobic residue V169 in the human A₃ receptor; and the other in TM6, occupied by H250/H251 in human A_2A and A₁ receptors and by a less bulky S247 in the A₃ receptor. In the end, these findings could help to design new subtype-selective adenosine receptor ligands. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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7 pages, 939 KiB

Open AccessCommunication

Namodenoson Inhibits the Growth of Pancreatic Carcinoma via Deregulation of the Wnt/β-catenin, NF-κB, and RAS Signaling Pathways

by Inbal Itzhak, Avital Bareket-Samish and Pnina Fishman

Biomolecules 2023, 13(11), 1584; https://doi.org/10.3390/biom13111584 - 27 Oct 2023

Viewed by 949

Abstract

Namodenoson, an A₃ adenosine receptor (A₃AR) agonist, is currently being used in a phase III trial in advanced liver cancer. We examined the anti-growth effect of namodenoson on pancreatic carcinoma cells and investigated the molecular mechanism involved. BxPC-3 pancreatic carcinoma cells were cultured with namodenoson (5–20 nM for 24 h at 37 °C), and the Presto Blue assay was used to monitor cell growth. Western blot analyses were performed on BxPC-3 cells (20 nM namodenoson for 24 h at 37 °C) to evaluate the expression levels of cell growth regulatory proteins. In vivo studies involved the subcutaneous inoculation of BxPC-3 cells into nude mice, randomizing the mice into namodenoson (10 μg/kg twice daily for 35 days) vs. control, and monitoring tumor size twice weekly. Treatment with namodenoson was associated with the significant dose-dependent inhibition of BxPC-3 cell growth, which was mitigated by the A₃AR antagonist MRS1523. Western blot analyses showed that namodenoson treatment modulated the expression of NF-κB, as well as proteins in the Wnt/β-catenin and the RAS signaling pathways, leading to the upregulation of apoptotic proteins (Bad, Bax). In vivo studies also showed the significant inhibition of pancreatic carcinoma tumor growth with namodenoson. In conclusion, our findings support the continued development of namodenoson as a treatment for pancreatic cancer. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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11 pages, 1751 KiB

Open AccessArticle

Functional Interaction between Adenosine A_2A and mGlu₅ Receptors Mediates STEP Phosphatase Activation and Promotes STEP/mGlu₅R Binding in Mouse Hippocampus and Neuroblastoma Cell Line

by Cinzia Mallozzi, Rita Pepponi, Lucia Gaddini, Ida Casella, Valentina Chiodi, Patrizia Popoli and Maria Rosaria Domenici

Biomolecules 2023, 13(9), 1350; https://doi.org/10.3390/biom13091350 - 05 Sep 2023

Viewed by 776

Abstract

(1) Background: Recently, we found that adenosine A_2A receptor (A_2AR) stimulation results in an increase in STEP phosphatase activity. In order to delve into the mechanism through which A_2AR stimulation induced STEP activation, we investigated the involvement of mGlu₅R since it is well documented that A_2AR and mGlu₅R physically and functionally interact in several brain areas. (2) Methods: In a neuroblastoma cell line (SH-SY5Y) and in mouse hippocampal slices, we evaluated the enzymatic activity of STEP by using a para-nitrophenyl phosphate colorimetric assay. A co-immunoprecipitation assay and a Western blot analysis were used to evaluate STEP/mGlu₅R binding. (3) Results: We found that the A_2AR-dependent activation of STEP was mediated by the mGlu₅R. Indeed, the A_2AR agonist CGS 21680 significantly increased STEP activity, and this effect was prevented not only by the A_2AR antagonist ZM 241385, as expected, but also by the mGlu₅R antagonist MPEP. In addition, we found that mGlu₅R agonist DHPG-induced STEP activation was reversed not only by the mGlu₅R antagonist MPEP but also by ZM 241385. Finally, via co-immunoprecipitation experiments, we found that mGlu₅R and STEP physically interact when both receptors are activated (4) Conclusions: These results demonstrated a close functional interaction between mGlu₅ and A_2A receptors in the modulation of STEP activity. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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14 pages, 2074 KiB

Open AccessEditor’s ChoiceArticle

Pharmacological Characterization of P626, a Novel Dual Adenosine A_2A/A_2B Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus

by Martina Venturini, Federica Cherchi, Clara Santalmasi, Lucia Frulloni, Ilaria Dettori, Daniela Catarzi, Felicita Pedata, Vittoria Colotta, Flavia Varano, Elisabetta Coppi and Anna Maria Pugliese

Biomolecules 2023, 13(6), 894; https://doi.org/10.3390/biom13060894 - 27 May 2023

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Abstract

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (A₁AR, A_2AAR, A_2BAR, A₃AR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of A_2AAR or A_2BAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus. Furthermore, the stimulation of A_2AARs or A_2BARs by respective selective agonists, CGS21680 and BAY60-6583, increases pre-synaptic neurotransmitter release, as shown by the decrease in paired-pulse facilitation (PPF) at Schaffer collateral-CA1 synapses. In the present research, we investigated the effect/s of the newly synthesized dual A_2AAR/A_2BAR antagonist, P626, in preventing A_2AAR- and/or A_2BAR-mediated effects by extracellular recordings of synaptic potentials in the CA1 rat hippocampal slices. We demonstrated that P626 prevented PPF reduction induced by CGS21680 or BAY60-6583 and delayed, in a concentration-dependent manner, AD appearance during a severe OGD. In conclusion, P626 may represent a putative neuroprotective compound for stroke treatment with the possible translational advantage of reducing side effects and bypassing differences in pharmacokinetics due to combined treatment. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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15 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

Adenosine A_2A Receptors Shut Down Adenosine A₁ Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation

by Cátia R. Lopes, Francisco Q. Gonçalves, Simão Olaio, Angelo R. Tomé, Rodrigo A. Cunha and João Pedro Lopes

Biomolecules 2023, 13(4), 715; https://doi.org/10.3390/biom13040715 - 21 Apr 2023

Cited by 5 | Viewed by 1490

Abstract

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A₁ and A_2A receptors (A₁R, A_2AR), respectively. Supramaximal activation of A₁R can block hippocampal synaptic transmission, and the tonic engagement of A₁R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A_2AR activation decreases A₁R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A₁R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A_2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A_2AR with CGS21680 (30 nM) decreased the potency of the A₁R agonist CPA (6–60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A_2AR play a key role in dampening A₁R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A₁R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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12 pages, 2224 KiB

Open AccessArticle

Synthesis and Effect of Conformationally Locked Carbocyclic Guanine Nucleotides on Dynamin

by Kiran S. Toti, John R. Jimah, Veronica Salmaso, Jenny E. Hinshaw and Kenneth A. Jacobson

Biomolecules 2022, 12(4), 584; https://doi.org/10.3390/biom12040584 - 16 Apr 2022

Viewed by 2322

Abstract

Guanine nucleotides can flip between a North and South conformation in the ribose moiety. To test the enzymatic activity of GTPases bound to nucleotides in the two conformations, we generated methanocarba guanine nucleotides in the North or South envelope conformations, i.e., (N)-GTP and (S)-GTP, respectively. With dynamin as a model system, we examined the effects of (N)-GTP and (S)-GTP on dynamin-mediated membrane constriction, an activity essential for endocytosis. Dynamin membrane constriction and fission activity are dependent on GTP binding and hydrolysis, but the effect of the conformational state of the GTP nucleotide on dynamin activity is not known. After reconstituting dynamin-mediated lipid tubulation and membrane constriction in vitro, we observed via cryo-electron microscopy (cryo-EM) that (N)-GTP, but not (S)-GTP, enables the constriction of dynamin-decorated lipid tubules. These findings suggest that the activity of dynamin is dependent on the conformational state of the GTP nucleotide. However, a survey of nucleotide ribose conformations associated with dynamin structures in nature shows almost exclusively the (S)-conformation. The explanation for this mismatch of (N) vs. (S) required for GTP analogues in a dynamin-mediated process will be addressed in future studies. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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Review

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33 pages, 1488 KiB

Open AccessReview

Pharmacology of Adenosine Receptors: Recent Advancements

by Fabrizio Vincenzi, Silvia Pasquini, Chiara Contri, Martina Cappello, Manuela Nigro, Alessia Travagli, Stefania Merighi, Stefania Gessi, Pier Andrea Borea and Katia Varani

Biomolecules 2023, 13(9), 1387; https://doi.org/10.3390/biom13091387 - 14 Sep 2023

Cited by 6 | Viewed by 2451

Abstract

Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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15 pages, 1018 KiB

Open AccessEditor’s ChoiceReview

Caffeine for Prevention of Alzheimer’s Disease: Is the A_2A Adenosine Receptor Its Target?

by Stefania Merighi, Alessia Travagli, Manuela Nigro, Silvia Pasquini, Martina Cappello, Chiara Contri, Katia Varani, Fabrizio Vincenzi, Pier Andrea Borea and Stefania Gessi

Biomolecules 2023, 13(6), 967; https://doi.org/10.3390/biom13060967 - 08 Jun 2023

Cited by 3 | Viewed by 2041

Abstract

Alzheimer’s disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted “in vivo” and “in vitro” provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A_2A receptors (A_2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A_2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine’s antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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19 pages, 1589 KiB

Open AccessEditor’s ChoiceReview

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

by Marta Boccazzi, Stefano Raffaele, Thomas Zanettin, Maria P. Abbracchio and Marta Fumagalli

Biomolecules 2023, 13(5), 856; https://doi.org/10.3390/biom13050856 - 18 May 2023

Cited by 3 | Viewed by 1845

Abstract

With the umbrella term ‘neurodevelopmental disorders’ (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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5 pages, 995 KiB

Open AccessOpinion

Purines and Adenosine Receptors in Osteoarthritis

by Bruce N. Cronstein and Siddhesh R. Angle

Biomolecules 2023, 13(12), 1760; https://doi.org/10.3390/biom13121760 - 07 Dec 2023

Viewed by 1285

Abstract

OA is a common and debilitating condition that restricts mobility and diminishes the quality of life. Recent work indicates that the generation of adenosine at the cell surface is an important mediator of chondrocyte homeostasis, and topical application of adenosine in a slow-release form (liposomes) can halt the progression of OA and diminish the pain associated with OA. Here, we review the evidence indicating that adenosine, acting at A_2A receptors, plays a critical role in endogenous and exogenous treatment and reversal of OA. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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