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Adenosine Receptors
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Adenosine Receptors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (10 May 2017) | Viewed by 67352

Special Issue Editors

Prof. Dr. Francisco Ciruela

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Guest Editor
Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, Campus Bellvitge, IDIBELL, Universitat de Barcelona. Av. Feixa Llarga, s/n, 08907 L’Hospitalet de Llobregat, Spain
Interests: G protein-coupled receptors; adenosine receptors; neuropharmacology; neurological diseases; allosteric modulation; receptor-receptor interactions; psychiatric diseases
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Eddy Sotelo

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Guest Editor
Centro Singular de Investigación en Quı́mica Biológica y Materiales Moleculares (CIQUS) and Departamento de Quı́mica Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
Interests: medicinal chemistry; adenosine receptors; GPCRs; multicomponent reactions; GPCR-oligomerization; chemical probes; allosteric modulation; multi-target drug discovery; hit identification

Special Issue Information

Dear Colleagues,

Adenosine is a well-known neuromodulator in the central nervous system and has effects on other tissues like immune or circulatory systems. Its physiological actions are exerted through G protein-coupled adenosine receptors (AR), which, in turn, are expressed in a large variety of cells. Interestingly, selective agonists and antagonists for all four AR subtypes have been developed and its diagnostic and therapeutic utility is being pursued.

Using AR as a paradigm of purinergic GPCRs, in this Special Issue, we intended to provide the reader with the recent developments in AR ligands. Thus, the submissions of papers describing new molecules showing activity through AR are welcome. In addition, manuscripts describing new AR-based chemical tools or approaches for the study of adenosine function, prospective analysis for the therapeutic future of AR ligands, and reviews will be also taken into consideration. Finally, authors are encouraged to propose topics that will be evaluated accordingly. Overall, we hope that this timely focused issue summarizing our current knowledge on adenosine receptors ligands will be of interest to a wide range of readers of the journal.

Prof. Dr. Francisco Ciruela
Guest Editor

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.

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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

  • Medicinal Chemistry
  • Adenosine Receptor Ligands
  • Therapeutics
  • G protein-coupled receptors
  • Agonist
  • Antagonist
  • Clinical trials
  • Allosteric modulator

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Published Papers (9 papers)

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Editorial

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165 KiB  
Editorial
Special Issue: Adenosine Receptors
by Francisco Ciruela and Eddy Sotelo
Molecules 2017, 22(7), 1220; https://doi.org/10.3390/molecules22071220 - 20 Jul 2017
Cited by 4 | Viewed by 3582
Abstract
Nearly 90 years ago, Drury and Szent-Györgyi revealed that adenosine produced profound hypotension and bradycardia, and it affected kidney function in mammals [1]. [...]
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(This article belongs to the Special Issue Adenosine Receptors)

Research

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963 KiB  
Article
Methodical Challenges and a Possible Resolution in the Assessment of Receptor Reserve for Adenosine, an Agonist with Short Half-Life
by Judit Zsuga, Tamas Erdei, Katalin Szabó, Nora Lampe, Csaba Papp, Akos Pinter, Andras Jozsef Szentmiklosi, Bela Juhasz, Zoltán Szilvássy and Rudolf Gesztelyi
Molecules 2017, 22(5), 839; https://doi.org/10.3390/molecules22050839 - 19 May 2017
Cited by 14 | Viewed by 5464
Abstract
The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation [...] Read more.
The term receptor reserve, first introduced and used in the traditional receptor theory, is an integrative measure of response-inducing ability of the interaction between an agonist and a receptor system (consisting of a receptor and its downstream signaling). The underlying phenomenon, i.e., stimulation of a submaximal fraction of receptors can apparently elicit the maximal effect (in certain cases), provides an opportunity to assess the receptor reserve. However, determining receptor reserve is challenging for agonists with short half-lives, such as adenosine. Although adenosine metabolism can be inhibited several ways (in order to prevent the rapid elimination of adenosine administered to construct concentration–effect (E/c) curves for the determination), the consequent accumulation of endogenous adenosine biases the results. To address this problem, we previously proposed a method, by means of which this bias can be mathematically corrected (utilizing a traditional receptor theory-independent approach). In the present investigation, we have offered in silico validation of this method by simulating E/c curves with the use of the operational model of agonism and then by evaluating them using our method. We have found that our method is suitable to reliably assess the receptor reserve for adenosine in our recently published experimental setting, suggesting that it may be capable for a qualitative determination of receptor reserve for rapidly eliminating agonists in general. In addition, we have disclosed a possible interference between FSCPX (8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)benzoyloxy)propyl]-N1-propylxanthine), an irreversible A1 adenosine receptor antagonist, and NBTI (S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine), a nucleoside transport inhibitor, i.e., FSCPX may blunt the effect of NBTI. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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4232 KiB  
Article
Supporting the Identification of Novel Fragment-Based Positive Allosteric Modulators Using a Supervised Molecular Dynamics Approach: A Retrospective Analysis Considering the Human A2A Adenosine Receptor as a Key Example
by Giuseppe Deganutti and Stefano Moro
Molecules 2017, 22(5), 818; https://doi.org/10.3390/molecules22050818 - 16 May 2017
Cited by 16 | Viewed by 5230
Abstract
Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal [...] Read more.
Structure-driven fragment-based (SDFB) approaches have provided efficient methods for the identification of novel drug candidates. This strategy has been largely applied in discovering several pharmacological ligand classes, including enzyme inhibitors, receptor antagonists and, more recently, also allosteric (positive and negative) modulators. Recently, Siegal and collaborators reported an interesting study, performed on a detergent-solubilized StaR adenosine A2A receptor, describing the existence of both fragment-like negative allosteric modulators (NAMs), and fragment-like positive allosteric modulators (PAMs). From this retrospective study, our results suggest that Supervised Molecular Dynamics (SuMD) simulations can support, on a reasonable time scale, the identification of fragment-like PAMs following their receptor recognition pathways and characterizing the possible allosteric binding sites. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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1259 KiB  
Article
Expression of Adenosine A2B Receptor and Adenosine Deaminase in Rabbit Gastric Mucosa ECL Cells
by Rosa María Arin, Ana Isabel Vallejo, Yuri Rueda, Olatz Fresnedo and Begoña Ochoa
Molecules 2017, 22(4), 625; https://doi.org/10.3390/molecules22040625 - 12 Apr 2017
Cited by 9 | Viewed by 8561
Abstract
Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal [...] Read more.
Adenosine is readily available to the glandular epithelium of the stomach. Formed continuously in intracellular and extracellular locations, it is notably produced from ATP released in enteric cotransmission. Adenosine analogs modulate chloride secretion in gastric glands and activate acid secretion in isolated parietal cells through A2B adenosine receptor (A2BR) binding. A functional link between surface A2BR and adenosine deaminase (ADA) was found in parietal cells, but whether this connection is a general feature of gastric mucosa cells is unknown. Here we examine whether A2BR is expressed at the membrane of histamine-producing enterochromaffin-like (ECL) cells, the major endocrine cell type in the oxyntic mucosa, and if so, whether it has a vicinity relationship with ADA. We used a highly homogeneous population of rabbit ECL cells (size 7.5–10 µm) after purification by elutriation centrifugation. The surface expression of A2BR and ADA proteins was assessed by flow cytometry and confocal microscopy. Our findings demonstrate that A2BR and ADA are partially coexpressed at the gastric ECL cell surface and that A2BR is functional, with regard to binding of adenosine analogs and adenylate cyclase activation. The physiological relevance of A2BR and ADA association in regulating histamine release is yet to be explained. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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1077 KiB  
Article
Synthesis and Characterization of a New Bivalent Ligand Combining Caffeine and Docosahexaenoic Acid
by Víctor Fernández-Dueñas, Jhonny Azuaje, Xavier Morató, Begoña Cordobilla, Joan Carles Domingo, Eddy Sotelo and Francisco Ciruela
Molecules 2017, 22(3), 366; https://doi.org/10.3390/molecules22030366 - 27 Feb 2017
Cited by 5 | Viewed by 6181
Abstract
Caffeine is a promising drug for the management of neurodegenerative diseases such as Parkinson’s disease (PD), demonstrating neuroprotective properties that have been attributed to its interaction with the basal ganglia adenosine A2A receptor (A2AR). However, the doses needed to exert these neuroprotective effects [...] Read more.
Caffeine is a promising drug for the management of neurodegenerative diseases such as Parkinson’s disease (PD), demonstrating neuroprotective properties that have been attributed to its interaction with the basal ganglia adenosine A2A receptor (A2AR). However, the doses needed to exert these neuroprotective effects may be too high. Thus, it is important to design novel approaches that selectively deliver this natural compound to the desired target. Docosahexaenoic acid (DHA) is the major omega-3 fatty acid in the brain and can act as a specific carrier of caffeine. Furthermore, DHA displays properties that may lead to its use as a neuroprotective agent. In the present study, we constructed a novel bivalent ligand covalently linking caffeine and DHA and assessed its pharmacological activity and safety profile in a simple cellular model. Interestingly, the new bivalent ligand presented higher potency as an A2AR inverse agonist than caffeine alone. We also determined the range of concentrations inducing toxicity both in a heterologous system and in primary striatal cultures. The novel strategy presented here of attaching DHA to caffeine may enable increased effects of the drug at desired sites, which could be of interest for the treatment of PD. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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Review

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3740 KiB  
Review
Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases
by Werner J. Geldenhuys, Ahmad Hanif, June Yun and Mohammed A. Nayeem
Molecules 2017, 22(6), 917; https://doi.org/10.3390/molecules22060917 - 1 Jun 2017
Cited by 20 | Viewed by 6124
Abstract
Cardiovascular diseases remain the number one diseases affecting patients’ morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected [...] Read more.
Cardiovascular diseases remain the number one diseases affecting patients’ morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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305 KiB  
Review
The Adenosinergic System as a Therapeutic Target in the Vasculature: New Ligands and Challenges
by Joana Beatriz Sousa and Carmen Diniz
Molecules 2017, 22(5), 752; https://doi.org/10.3390/molecules22050752 - 6 May 2017
Cited by 27 | Viewed by 5331
Abstract
Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors—A1, A2A, [...] Read more.
Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors—A1, A2A, A2B and A3—have been identified. Adenosine receptors are membrane G-protein receptors that trigger their actions through several signaling pathways and present differential affinity requirements. Adenosine is an endogenous ligand whose extracellular levels can reach concentrations high enough to activate the adenosine receptors. This nucleoside is a product of enzymatic breakdown of extra and intracellular adenine nucleotides and also of S-adenosylhomocysteine. Adenosine availability is also dependent on the activity of nucleoside transporters (NTs). The interplay between NTs and adenosine receptors’ activities are debated and a particular attention is given to the paramount importance of the disruption of this interplay in vascular pathophysiology, namely in hypertension., The integration of important functional aspects of individual adenosine receptor pharmacology (such as in vasoconstriction/vasodilation) and morphological features (within the three vascular layers) in vessels will be discussed, hopefully clarifying the importance of adenosine receptors/NTs for modulating peripheral mesenteric vascular resistance. In recent years, an increase interest in purine physiology/pharmacology has led to the development of new ligands for adenosine receptors. Some of them have been patented as having promising therapeutic activities and some have been chosen to undergo on clinical trials. Increased levels of endogenous adenosine near a specific subtype can lead to its activation, constituting an indirect receptor targeting approach either by inhibition of NT or, alternatively, by increasing the activity of enzymes responsible for ATP breakdown. These findings highlight the putative role of adenosinergic players as attractive therapeutic targets for cardiovascular pathologies, namely hypertension, heart failure or stroke. Nevertheless, several aspects are still to be explored, creating new challenges to be addressed in future studies, particularly the development of strategies able to circumvent the predicted side effects of these therapies. Full article
(This article belongs to the Special Issue Adenosine Receptors)
5360 KiB  
Review
Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration
by Jocelyn Stockwell, Elisabet Jakova and Francisco S. Cayabyab
Molecules 2017, 22(4), 676; https://doi.org/10.3390/molecules22040676 - 23 Apr 2017
Cited by 147 | Viewed by 17024
Abstract
The inhibitory adenosine A1 receptor (A1R) and excitatory A2A receptor (A2AR) are predominantly expressed in the brain. Whereas the A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases, the inhibitory A1R has traditionally been ascribed to have a [...] Read more.
The inhibitory adenosine A1 receptor (A1R) and excitatory A2A receptor (A2AR) are predominantly expressed in the brain. Whereas the A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases, the inhibitory A1R has traditionally been ascribed to have a neuroprotective function in various brain insults. This review provides a summary of the emerging role of prolonged A1R signaling and its potential cross-talk with A2AR in the cellular basis for increased neurotoxicity in neurodegenerative disorders. This A1R signaling enhances A2AR-mediated neurodegeneration, and provides a platform for future development of neuroprotective agents in stroke, Parkinson’s disease and epilepsy. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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2382 KiB  
Review
Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding
by Antonella Ciancetta and Kenneth A. Jacobson
Molecules 2017, 22(3), 449; https://doi.org/10.3390/molecules22030449 - 11 Mar 2017
Cited by 28 | Viewed by 8907
Abstract
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A3 [...] Read more.
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A1, A2A, A2B and A3, which belong to the G protein-coupled receptor (GPCR) superfamily. The human A3AR (hA3AR) subtype is implicated in several cytoprotective functions. Therefore, hA3AR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anticancer, and cardioprotective agents. Structure-based molecular modeling techniques have been applied over the years to rationalize the structure–activity relationships (SARs) of newly emerged A3AR ligands, guide the subsequent lead optimization, and interpret site-directed mutagenesis (SDM) data from a molecular perspective. In this review, we showcase selected modeling-based and guided strategies that were applied to elucidate the binding of agonists to the A3AR and discuss the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates. Full article
(This article belongs to the Special Issue Adenosine Receptors)
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