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Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 55903

Special Issue Editors

Dr. Anna Junker

E-Mail Website
Guest Editor
European Institute of Molecular Imaging, University of Münster, D-48149 Münster, Germany
Interests: subtype-specific P2Y and P2X receptor ligands; CD73 inhibitors; PET tracers and optical imaging agents
Dr. Antonella Ciancetta

E-Mail
Guest Editor
Department of Chemical, Pharmaceutical and Agricultural Sciences; University of Ferrara, 44121 Ferrara, Italy
Interests: computer-aided drug design; GPCR allosteric modulation; dimerization; biased signaling; structure-based design of peptide GPCR binders
Dr. Jinha Yu

E-Mail Website
Guest Editor
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Women University, Seoul 03760, Korea
Interests: drug discovery and design; small molecule design; adenosine receptor ligands; modified nucleosides

Special Issue Information

Dear Colleagues,

Dr. K. A. Jacobson is the John W. Daly Distinguished Scientist, Senior Investigator and Chief of the Molecular Recognition Section, Laboratory of Bioorganic Chemistry (NIDDK, NIH, Bethesda, USA). He earned his B.A. from Reed College (1975) and his Ph.D. in Chemistry with Murray Goodman at the University of California, San Diego (1981). He completed postdoctoral studies in organic chemistry at the Weizmann Institute and joined NIH in 1983, subsequently becoming a tenured Research Chemist (1988), Section Chief (since 1993), Senior Investigator (since 2003), and Lab Chief (2008–2018).

Dr. Jacobson is a pioneer in the field of ligand design and pharmacology of adenosine (P1) and P2 receptors. His numerous contributions include the first molecular model of adenosine receptors in 1992 and first publication on modeling the involvement of the 2nd extracellular loop of GPCRs in small molecule recognition. He introduced many of the first selective and high affinity agonists/antagonists (including fluorescent ligands and unique affinity labels) for adenosine, P2Y, and P2X receptors and developed the first selective, competitive antagonists for A1, A2B, A3, P2Y1, and P2Y13 receptors and positive allosteric modulators (PAMs) for A3 and P2X1 receptors. More than 36 compounds introduced by Jacobson and coworkers are available commercially as research tools. Five biopharma startups were founded based on the therapeutic potential of compounds from the Jacobson lab. Two selective A3 adenosine agonists invented by Dr. Jacobson are being developed by the pharmaceutical industry and are in Phase II or III clinical trials for liver cancer, NASH, psoriasis, and other inflammatory diseases. A third A3 agonist is licensed for pharma development for pain treatment. In collaboration with Ray Stevens (University of Southern California), he also contributed to the determination of the first X-ray crystal structures of P2Y and agonist-bound A2A receptors.

Dr. Jacobson is a Fellow of the American Chemical Society and served as Chair of the Medicinal Chemistry Div. He mentored approximately 70 postdoctoral fellows throughout his career and authored more than 800 scientific publications (H-index of 109). As inventor of >60 patents on new receptor ligands and analytical methods, filed in the US and other countries, he was highlighted as a Featured NIDDK Innovator from the Office of Technology Transfer and Development.

His numerous awards include the Medicinal Chemistry Hall of Fame (2009), Philip S. Portoghese Medicinal Chemistry Award (2012), and Smissman Award (2017), all from the Medicinal Chemistry Div. of the American Chemical Soc. Other awards include the Sato Memorial International Award of the Pharmaceutical Soc. of Japan (2009), ASPET Goodman and Gilman Award in Drug Receptor Pharmacology (2014), and World’s Most Influential Scientific Minds, Pharmacology and Toxicology (2016, Thomson Reuters).

This Special Issue of Molecules is dedicated to Dr. K. A. Jacobson’s being awarded the first Tu Youyou Award (2017) to honor his great contributions and extraordinary research achievements.

Dr. Anna Junker
Dr. Antonella Ciancetta
Dr. Jinha Yu
Guest Editors

Manuscript Submission Information

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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. Molecules 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

  • Purinergic signaling 
  • Adenosine receptors (P1) 
  • P2Y 
  • P2X 
  • ecto-5′-nucleotidase, CD73 
  • Ectonucleoside triphosphate diphosphohydrolase, CD39 
  • Ectonucleotide pyrophosphatase/phosphodiesterase, CD203 
  • GPCR structure 
  • Nucleosides 
  • Nucleotides

Published Papers (21 papers)

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Research

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19 pages, 3129 KiB  
Article
Cancer-Associated Mutations of the Adenosine A2A Receptor Have Diverse Influences on Ligand Binding and Receptor Functions
by Chenlin Feng, Xuesong Wang, Willem Jespers, Rongfang Liu, Sofía Denise Zamarbide Losada, Marina Gorostiola González, Gerard J. P. van Westen, Erik H. J. Danen and Laura H. Heitman
Molecules 2022, 27(15), 4676; https://doi.org/10.3390/molecules27154676 - 22 Jul 2022
Cited by 2 | Viewed by 2008
Abstract
The adenosine A2A receptor (A2AAR) is a class A G-protein-coupled receptor (GPCR). It is an immune checkpoint in the tumor micro-environment and has become an emerging target for cancer treatment. In this study, we aimed to explore the effects of [...] Read more.
The adenosine A2A receptor (A2AAR) is a class A G-protein-coupled receptor (GPCR). It is an immune checkpoint in the tumor micro-environment and has become an emerging target for cancer treatment. In this study, we aimed to explore the effects of cancer-patient-derived A2AAR mutations on ligand binding and receptor functions. The wild-type A2AAR and 15 mutants identified by Genomic Data Commons (GDC) in human cancers were expressed in HEK293T cells. Firstly, we found that the binding affinity for agonist NECA was decreased in six mutants but increased for the V275A mutant. Mutations A165V and A265V decreased the binding affinity for antagonist ZM241385. Secondly, we found that the potency of NECA (EC50) in an impedance-based cell-morphology assay was mostly correlated with the binding affinity for the different mutants. Moreover, S132L and H278N were found to shift the A2AAR towards the inactive state. Importantly, we found that ZM241385 could not inhibit the activation of V275A and P285L stimulated by NECA. Taken together, the cancer-associated mutations of A2AAR modulated ligand binding and receptor functions. This study provides fundamental insights into the structure–activity relationship of the A2AAR and provides insights for A2AAR-related personalized treatment in cancer. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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19 pages, 4350 KiB  
Article
Design, Synthesis and Biological Evaluation of 1,3,5-Triazine Derivatives Targeting hA1 and hA3 Adenosine Receptor
by Sujin Park, Yujin Ahn, Yongchan Kim, Eun Joo Roh, Yoonji Lee, Chaebin Han, Hee Min Yoo and Jinha Yu
Molecules 2022, 27(13), 4016; https://doi.org/10.3390/molecules27134016 - 22 Jun 2022
Cited by 3 | Viewed by 1771
Abstract
Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, [...] Read more.
Adenosine mediates various physiological activities in the body. Adenosine receptors (ARs) are widely expressed in tumors and the tumor microenvironment (TME), and they induce tumor proliferation and suppress immune cell function. There are four types of human adenosine receptor (hARs): hA1, hA2A, hA2B, and hA3. Both hA1 and hA3 AR play an important role in tumor proliferation. We designed and synthesized novel 1,3,5-triazine derivatives through amination and Suzuki coupling, and evaluated them for binding affinities to each hAR subtype. Compounds 9a and 11b showed good binding affinity to both hA1 and hA3 AR, while 9c showed the highest binding affinity to hA1 AR. In this study, we discovered that 9c inhibits cell viability, leading to cell death in lung cancer cell lines. Flow cytometry analysis revealed that 9c caused an increase in intracellular reactive oxygen species (ROS) and a depolarization of the mitochondrial membrane potential. The binding mode of 1,3,5-triazine derivatives to hA1 and hA3 AR were predicted by a molecular docking study. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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16 pages, 2684 KiB  
Article
Irreversible Antagonists for the Adenosine A2B Receptor
by Ahmed Temirak, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaaßen, Christin Vielmuth, Tobias Claff and Christa E. Müller
Molecules 2022, 27(12), 3792; https://doi.org/10.3390/molecules27123792 - 13 Jun 2022
Cited by 5 | Viewed by 2381
Abstract
Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding [...] Read more.
Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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17 pages, 22799 KiB  
Article
Cancer-Related Somatic Mutations in Transmembrane Helices Alter Adenosine A1 Receptor Pharmacology
by Xuesong Wang, Willem Jespers, Kim A. N. Wolff, Jill Buytelaar, Adriaan P. IJzerman, Gerard J. P. van Westen and Laura H. Heitman
Molecules 2022, 27(12), 3742; https://doi.org/10.3390/molecules27123742 - 10 Jun 2022
Cited by 2 | Viewed by 1561
Abstract
Overexpression of the adenosine A1 receptor (A1AR) has been detected in various cancer cell lines. However, the role of A1AR in tumor development is still unclear. Thirteen A1AR mutations were identified in the Cancer Genome Atlas [...] Read more.
Overexpression of the adenosine A1 receptor (A1AR) has been detected in various cancer cell lines. However, the role of A1AR in tumor development is still unclear. Thirteen A1AR mutations were identified in the Cancer Genome Atlas from cancer patient samples. We have investigated the pharmacology of the mutations located at the 7-transmembrane domain using a yeast system. Concentration–growth curves were obtained with the full agonist CPA and compared to the wild type hA1AR. H78L3.23 and S246T6.47 showed increased constitutive activity, while only the constitutive activity of S246T6.47 could be reduced to wild type levels by the inverse agonist DPCPX. Decreased constitutive activity was observed on five mutant receptors, among which A52V2.47 and W188C5.46 showed a diminished potency for CPA. Lastly, a complete loss of activation was observed in five mutant receptors. A selection of mutations was also investigated in a mammalian system, showing comparable effects on receptor activation as in the yeast system, except for residues pointing toward the membrane. Taken together, this study will enrich the view of the receptor structure and function of A1AR, enlightening the consequences of these mutations in cancer. Ultimately, this may provide an opportunity for precision medicine for cancer patients with pathological phenotypes involving these mutations. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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14 pages, 1998 KiB  
Article
Cholesterol Dependent Activity of the Adenosine A2A Receptor Is Modulated via the Cholesterol Consensus Motif
by Claire McGraw, Kirsten Swonger Koretz, Daniel Oseid, Edward Lyman and Anne Skaja Robinson
Molecules 2022, 27(11), 3529; https://doi.org/10.3390/molecules27113529 - 31 May 2022
Cited by 5 | Viewed by 1878
Abstract
Background: Membrane cholesterol dysregulation has been shown to alter the activity of the adenosine A2A receptor (A2AR), a G protein-coupled receptor, thereby implicating cholesterol levels in diseases such as Alzheimer’s and Parkinson’s. A limited number of A2AR crystal [...] Read more.
Background: Membrane cholesterol dysregulation has been shown to alter the activity of the adenosine A2A receptor (A2AR), a G protein-coupled receptor, thereby implicating cholesterol levels in diseases such as Alzheimer’s and Parkinson’s. A limited number of A2AR crystal structures show the receptor interacting with cholesterol, as such molecular simulations are often used to predict cholesterol interaction sites. Methods: Here, we use experimental methods to determine whether a specific interaction between amino acid side chains in the cholesterol consensus motif (CCM) of full length, wild-type human A2AR, and cholesterol modulates activity of the receptor by testing the effects of mutational changes on functional consequences, including ligand binding, G protein coupling, and downstream activation of cyclic AMP. Results and conclusions: Our data, taken with previously published studies, support a model of receptor state-dependent binding between cholesterol and the CCM, whereby cholesterol facilitates both G protein coupling and downstream signaling of A2AR. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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22 pages, 3892 KiB  
Article
A2A Adenosine Receptor Antagonists: Are Triazolotriazine and Purine Scaffolds Interchangeable?
by Andrea Spinaci, Catia Lambertucci, Michela Buccioni, Diego Dal Ben, Claudia Graiff, Maria Cristina Barbalace, Silvana Hrelia, Cristina Angeloni, Seyed Khosrow Tayebati, Massimo Ubaldi, Alessio Masi, Karl-Norbert Klotz, Rosaria Volpini and Gabriella Marucci
Molecules 2022, 27(8), 2386; https://doi.org/10.3390/molecules27082386 - 07 Apr 2022
Cited by 5 | Viewed by 1876
Abstract
The A2A adenosine receptor (A2AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A2AAR ligands, two [...] Read more.
The A2A adenosine receptor (A2AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A2AAR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A2AAR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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38 pages, 4675 KiB  
Article
Development of Bicyclo[3.1.0]hexane-Based A3 Receptor Ligands: Closing the Gaps in the Structure–Affinity Relationships
by Jan Phillip Lemmerhirt, Andreas Isaak, Rongfang Liu, Max Kock, Constantin G. Daniliuc, Kenneth A. Jacobson, Laura H. Heitman and Anna Junker
Molecules 2022, 27(7), 2283; https://doi.org/10.3390/molecules27072283 - 31 Mar 2022
Cited by 2 | Viewed by 2550
Abstract
The adenosine A3 receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at [...] Read more.
The adenosine A3 receptor is a promising target for treating and diagnosing inflammation and cancer. In this paper, a series of bicyclo[3.1.0]hexane-based nucleosides was synthesized and evaluated for their P1 receptor affinities in radioligand binding studies. The study focused on modifications at 1-, 2-, and 6-positions of the purine ring and variations of the 5′-position at the bicyclo[3.1.0]hexane moiety, closing existing gaps in the structure–affinity relationships. The most potent derivative 30 displayed moderate A3AR affinity (Ki of 0.38 μM) and high A3R selectivity. A subset of compounds varied at 5′-position was further evaluated in functional P2Y1R assays, displaying no off-target activity. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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18 pages, 2119 KiB  
Article
Untargeted Metabolomics Reveals the Potential Antidepressant Activity of a Novel Adenosine Receptor Antagonist
by Arnold Petrus Smith, Jeremie Zander Lindeque and Mietha Magdalena van der Walt
Molecules 2022, 27(7), 2094; https://doi.org/10.3390/molecules27072094 - 24 Mar 2022
Cited by 1 | Viewed by 1873
Abstract
Depression is the most common mental illness, affecting approximately 4.4% of the global population. Despite many available treatments, some patients exhibit treatment-resistant depression. Thus, the need to develop new and alternative treatments cannot be overstated. Adenosine receptor antagonists have emerged as a promising [...] Read more.
Depression is the most common mental illness, affecting approximately 4.4% of the global population. Despite many available treatments, some patients exhibit treatment-resistant depression. Thus, the need to develop new and alternative treatments cannot be overstated. Adenosine receptor antagonists have emerged as a promising new class of antidepressants. The current study investigates a novel dual A1/A2A adenosine receptor antagonist, namely 2-(3,4-dihydroxybenzylidene)-4-methoxy-2,3-dihydro-1H-inden-1-one (1a), for antidepressant capabilities by determining its metabolic profiles and comparing them to those of two reference compounds (imipramine and KW-6002). The metabolic profiles were obtained by treating male Sprague-Dawley rats with 1a and the reference compounds and subjecting them to the forced swim test. Serum and brain material was consequently collected from the animals following euthanasia, after which the metabolites were extracted and analyzed through untargeted metabolomics using both 1H-NMR and GC-TOFMS. The current study provides insight into compound 1a’s metabolic profile. The metabolic profile of 1a was similar to those of the reference compounds. They potentially exhibit their antidepressive capabilities via downstream effects on amino acid and lipid metabolism. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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11 pages, 2938 KiB  
Article
Molecular and Pharmacological Evidence for the Expression of Multiple Functional P2 Purinergic Receptors in Human Adipocytes
by Marco Rossato, Francesca Favaretto, Marnie Granzotto, Marika Crescenzi, Alessandra Boscaro, Angelo Di Vincenzo, Federico Capone, Edoardo Dalla Nora, Eva Zabeo and Roberto Vettor
Molecules 2022, 27(6), 1913; https://doi.org/10.3390/molecules27061913 - 16 Mar 2022
Cited by 4 | Viewed by 1625
Abstract
Extracellular ATP exerts important functions as an extracellular signaling molecule via the activation of specific P2 purinergic receptors (P2X and P2Y). We investigated the expression of the different P2 receptors and their possible functional activation in human adipocytes in primary culture. We performed [...] Read more.
Extracellular ATP exerts important functions as an extracellular signaling molecule via the activation of specific P2 purinergic receptors (P2X and P2Y). We investigated the expression of the different P2 receptors and their possible functional activation in human adipocytes in primary culture. We performed molecular expression analysis of the P2 receptors in human mature adipocytes; examined their functional activation by different nucleotides evaluating [Ca2+]i modifications and IL-6 secretion, and determined the ability of adipocytes to release ATP in the extracellular medium. Human adipocytes express different P2X and P2Y receptors. Extracellular ATP elicited a rise in [Ca2+]i via the activation of P2X and P2Y receptor subtypes. Human adipocytes spontaneously released ATP in the extracellular medium and secreted IL-6 both at rest and after stimulation with ATP. This stimulatory effect of ATP on IL-6 secretion was inhibited by pre-incubation with apyrase, an ATP metabolizing enzyme. These results demonstrate that human adipocytes express different P2X and P2Y receptors that are functionally activated by extracellular nucleotides. Furthermore, human adipocytes spontaneously release ATP, which can act in an autocrine/paracrine fashion on adipocytes, possibly participating in the regulation of inflammatory cytokine release. Thus, P2 purinergic receptors could be a potential therapeutic target to contrast the inflammatory and metabolic complications characterizing obesity. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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16 pages, 2978 KiB  
Article
Dihydropyridines Potentiate ATP-Induced Currents Mediated by the Full-Length Human P2X5 Receptor
by Ida C. Schiller, Kenneth A. Jacobson, Zhiwei Wen, Aparna Malisetty, Günther Schmalzing and Fritz Markwardt
Molecules 2022, 27(6), 1846; https://doi.org/10.3390/molecules27061846 - 11 Mar 2022
Cited by 4 | Viewed by 1989
Abstract
The P2X5 receptor, an ATP-gated cation channel, is believed to be involved in tumor development, inflammatory bone loss and inflammasome activation after bacterial infection. Therefore, it is a worthwhile pharmacological target to treat the corresponding diseases, especially in minority populations that have a [...] Read more.
The P2X5 receptor, an ATP-gated cation channel, is believed to be involved in tumor development, inflammatory bone loss and inflammasome activation after bacterial infection. Therefore, it is a worthwhile pharmacological target to treat the corresponding diseases, especially in minority populations that have a gene variant coding for functional homotrimeric P2X5 channels. Here, we investigated the effects of dihydropyridines on the human full-length P2X5 receptor (hP2X5FL) heterologously expressed in Xenopus oocytes using the two-microelectrode voltage clamp method. Agonist dependency, kinetics and permeation behavior, including Cl− permeability, were similar to hP2X5FL expressed in HEK293 or 1321N1 cells. Additionally, 1,4-dihydropyridines have been shown to interact with various other purinergic receptors, and we have examined them as potential hP2X5 modulators. Of seven commercially available and four newly synthesized dihydropyridines tested at hP2X5FL, only amlodipine exerted an inhibitory effect, but only at a high concentration of 300 µM. Isradipine and—even more—nimodipine stimulated ATP-induced currents in the low micromolar range. We conclude that common dihydropyridines or four new derivatives of amlodipine are not suitable as hP2X5 antagonists, but amlodipine might serve as a lead for future synthesis to increase its affinity. Furthermore, a side effect of nimodipine therapy could be a stimulatory effect on inflammatory processes. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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13 pages, 2375 KiB  
Article
Brain Iron Deficiency Changes the Stoichiometry of Adenosine Receptor Subtypes in Cortico-Striatal Terminals: Implications for Restless Legs Syndrome
by Matilde S. Rodrigues, Samira G. Ferreira, César Quiroz, Christopher J. Earley, Diego García-Borreguero, Rodrigo A. Cunha, Francisco Ciruela, Attila Köfalvi and Sergi Ferré
Molecules 2022, 27(5), 1489; https://doi.org/10.3390/molecules27051489 - 23 Feb 2022
Cited by 11 | Viewed by 2106
Abstract
Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. [...] Read more.
Brain iron deficiency (BID) constitutes a primary pathophysiological mechanism in restless legs syndrome (RLS). BID in rodents has been widely used as an animal model of RLS, since it recapitulates key neurochemical changes reported in RLS patients and shows an RLS-like behavioral phenotype. Previous studies with the BID-rodent model of RLS demonstrated increased sensitivity of cortical pyramidal cells to release glutamate from their striatal nerve terminals driving striatal circuits, a correlative finding of the cortical motor hyperexcitability of RLS patients. It was also found that BID in rodents leads to changes in the adenosinergic system, a downregulation of the inhibitory adenosine A1 receptors (A1Rs) and upregulation of the excitatory adenosine A2A receptors (A2ARs). It was then hypothesized, but not proven, that the BID-induced increased sensitivity of cortico-striatal glutamatergic terminals could be induced by a change in A1R/A2AR stoichiometry in favor of A2ARs. Here, we used a newly developed FACS-based synaptometric analysis to compare the relative abundance on A1Rs and A2ARs in cortico-striatal and thalamo-striatal glutamatergic terminals (labeled with vesicular glutamate transporters VGLUT1 and VGLUT2, respectively) of control and BID rats. It could be demonstrated that BID (determined by measuring transferrin receptor density in the brain) is associated with a selective decrease in the A1R/A2AR ratio in VGLUT1 positive-striatal terminals. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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15 pages, 3359 KiB  
Article
Synthesis and Structure–Activity Relationship Studies of Benzimidazole-4,7-dione-Based P2X3 Receptor Antagonists as Novel Anti-Nociceptive Agents
by Jinsu Bae, Yeo-Ok Kim, Xuehao Han, Myung-Ha Yoon, Woong-Mo Kim and Yong-Chul Kim
Molecules 2022, 27(4), 1337; https://doi.org/10.3390/molecules27041337 - 16 Feb 2022
Cited by 4 | Viewed by 2200
Abstract
P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has [...] Read more.
P2X3 receptors (P2X3R) are ATP-gated ion channels predominantly expressed in C- and Aδ-fiber primary afferent neurons and have been introduced as a novel therapeutic target for neurological disorders, including neuropathic pain and chronic cough. Because of its localized distribution, antagonism of P2X3R has been thoroughly considered, and the avoidance of issues related to CNS side effects has been proven in clinical trials. In this article, benzimidazole-4,7-dione-based derivatives were introduced as a new chemical entity for the development of P2X3R antagonists. Starting from the discovery of a hit compound from the screening of 8364 random library compounds in the Korea Chemical Bank, which had an IC50 value of 1030 nM, studies of structure–activity and structure–property relationships enabled further optimization toward improving the antagonistic activities as well as the drug’s physicochemical properties, including metabolic stability. As for the results, the final optimized compound 14h was developed with an IC50 value of 375 nM at P2X3R with more than 23-fold selectivity versus P2X2/3R, along with properties of metabolic stability and improved solubility. In neuropathic pain animal models evoked by either nerve ligation or chemotherapeutics in male Sprague-Dawley rats, compound 14h showed anti-nociceptive effects through an increase in the mechanical withdrawal threshold as measured by von Frey filament following intravenous administration. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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Review

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12 pages, 1215 KiB  
Review
Drugs Targeting the A3 Adenosine Receptor: Human Clinical Study Data
by Pnina Fishman
Molecules 2022, 27(12), 3680; https://doi.org/10.3390/molecules27123680 - 08 Jun 2022
Cited by 15 | Viewed by 3378
Abstract
The A3 adenosine receptor (A3AR) is overexpressed in pathological human cells. Piclidenoson and namodenoson are A3AR agonists with high affinity and selectivity to A3AR. Both induce apoptosis of cancer and inflammatory cells via a molecular mechanism entailing deregulation of the Wnt and the [...] Read more.
The A3 adenosine receptor (A3AR) is overexpressed in pathological human cells. Piclidenoson and namodenoson are A3AR agonists with high affinity and selectivity to A3AR. Both induce apoptosis of cancer and inflammatory cells via a molecular mechanism entailing deregulation of the Wnt and the NF-κB signaling pathways. Our company conducted phase I studies showing the safety of these 2 molecules. In the phase II studies in psoriasis patients, piclidenoson was safe and demonstrated efficacy manifested in significant improvements in skin lesions. Namodenoson is currently being developed to treat liver cancer, where prolonged overall survival was observed in patients with advanced liver disease and a Child–Pugh B score of 7. A pivotal phase III study in this patient population has been approved by the FDA and the EMA and is currently underway. Namodenoson is also being developed to treat non-alcoholic steatohepatitis (NASH). A Phase IIa study has been successfully concluded and showed that namodenoson has anti-inflammatory, anti-fibrosis, and anti-steatosis effects. A phase IIb study in NASH is currently enrolling patients. In conclusion, A3AR agonists are promising drug candidates in advanced stages of clinical development and demonstrate safety and efficacy in their targeted indications. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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9 pages, 539 KiB  
Review
P2X7 Receptors in Astrocytes: A Switch for Ischemic Tolerance
by Yuri Hirayama, Naohiko Anzai, Hiroyuki Kinouchi and Schuichi Koizumi
Molecules 2022, 27(12), 3655; https://doi.org/10.3390/molecules27123655 - 07 Jun 2022
Cited by 6 | Viewed by 1980
Abstract
A sub-lethal ischemic episode (preconditioning [PC]) protects neurons against a subsequent lethal ischemic injury. This phenomenon is known as ischemic tolerance. PC itself does not cause brain damage, but affects glial responses, especially astrocytes, and transforms them into an ischemia-resistant phenotype. P2X7 receptors [...] Read more.
A sub-lethal ischemic episode (preconditioning [PC]) protects neurons against a subsequent lethal ischemic injury. This phenomenon is known as ischemic tolerance. PC itself does not cause brain damage, but affects glial responses, especially astrocytes, and transforms them into an ischemia-resistant phenotype. P2X7 receptors (P2X7Rs) in astrocytes play essential roles in PC. Although P2X7Rs trigger inflammatory and toxic responses, PC-induced P2X7Rs in astrocytes function as a switch to protect the brain against ischemia. In this review, we focus on P2X7Rs and summarize recent developments on how astrocytes control P2X7Rs and what molecular mechanisms they use to induce ischemic tolerance. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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14 pages, 2949 KiB  
Review
G Protein-coupled Receptor (GPCR) Reconstitution and Labeling for Solution Nuclear Magnetic Resonance (NMR) Studies of the Structural Basis of Transmembrane Signaling
by Haoyi Ge, Huixia Wang, Benxun Pan, Dandan Feng, Canyong Guo, Lingyun Yang, Dongsheng Liu and Kurt Wüthrich
Molecules 2022, 27(9), 2658; https://doi.org/10.3390/molecules27092658 - 20 Apr 2022
Cited by 8 | Viewed by 3802
Abstract
G protein-coupled receptors (GPCRs) are a large membrane protein family found in higher organisms, including the human body. GPCRs mediate cellular responses to diverse extracellular stimuli and thus control key physiological functions, which makes them important targets for drug design. Signaling by GPCRs [...] Read more.
G protein-coupled receptors (GPCRs) are a large membrane protein family found in higher organisms, including the human body. GPCRs mediate cellular responses to diverse extracellular stimuli and thus control key physiological functions, which makes them important targets for drug design. Signaling by GPCRs is related to the structure and dynamics of these proteins, which are modulated by extrinsic ligands as well as by intracellular binding partners such as G proteins and arrestins. Here, we review some basics of using nuclear magnetic resonance (NMR) spectroscopy in solution for the characterization of GPCR conformations and intermolecular interactions that relate to transmembrane signaling. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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21 pages, 2915 KiB  
Review
The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson’s Disease
by Akihisa Mori, Jiang-Fan Chen, Shinichi Uchida, Cecile Durlach, Shelby M. King and Peter Jenner
Molecules 2022, 27(7), 2366; https://doi.org/10.3390/molecules27072366 - 06 Apr 2022
Cited by 21 | Viewed by 4639
Abstract
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase [...] Read more.
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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26 pages, 4357 KiB  
Review
Molecular Simulations and Drug Discovery of Adenosine Receptors
by Jinan Wang, Apurba Bhattarai, Hung N. Do, Sana Akhter and Yinglong Miao
Molecules 2022, 27(7), 2054; https://doi.org/10.3390/molecules27072054 - 22 Mar 2022
Cited by 4 | Viewed by 3218
Abstract
G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins. Four subtypes of adenosine receptors (ARs), the A1AR, A2AAR, A2BAR and A3AR, each with a unique pharmacological profile and distribution within the tissues [...] Read more.
G protein-coupled receptors (GPCRs) represent the largest family of human membrane proteins. Four subtypes of adenosine receptors (ARs), the A1AR, A2AAR, A2BAR and A3AR, each with a unique pharmacological profile and distribution within the tissues in the human body, mediate many physiological functions and serve as critical drug targets for treating numerous human diseases including cancer, neuropathic pain, cardiac ischemia, stroke and diabetes. The A1AR and A3AR preferentially couple to the Gi/o proteins, while the A2AAR and A2BAR prefer coupling to the Gs proteins. Adenosine receptors were the first subclass of GPCRs that had experimental structures determined in complex with distinct G proteins. Here, we will review recent studies in molecular simulations and computer-aided drug discovery of the adenosine receptors and also highlight their future research opportunities. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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Graphical abstract

17 pages, 2432 KiB  
Review
The Role of Microglial Purinergic Receptors in Pain Signaling
by Hidetoshi Tozaki-Saitoh, Hiroshi Takeda and Kazuhide Inoue
Molecules 2022, 27(6), 1919; https://doi.org/10.3390/molecules27061919 - 16 Mar 2022
Cited by 10 | Viewed by 4147
Abstract
Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety [...] Read more.
Pain is an essential modality of sensation in the body. Purinergic signaling plays an important role in nociceptive pain transmission, under both physiological and pathophysiological conditions, and is important for communication between both neuronal and non-neuronal cells. Microglia and astrocytes express a variety of purinergic effectors, and a variety of receptors play critical roles in the pathogenesis of neuropathic pain. In this review, we discuss our current knowledge of purinergic signaling and of the compounds that modulate purinergic transmission, with the aim of highlighting the importance of purinergic pathways as targets for the treatment of persistent pain. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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15 pages, 1112 KiB  
Review
Therapeutic Potential of Highly Selective A3 Adenosine Receptor Ligands in the Central and Peripheral Nervous System
by Elisabetta Coppi, Federica Cherchi, Martina Venturini, Elena Lucarini, Renato Corradetti, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Felicita Pedata and Anna Maria Pugliese
Molecules 2022, 27(6), 1890; https://doi.org/10.3390/molecules27061890 - 15 Mar 2022
Cited by 7 | Viewed by 3160
Abstract
Ligands of the Gi protein-coupled adenosine A3 receptor (A3R) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe [...] Read more.
Ligands of the Gi protein-coupled adenosine A3 receptor (A3R) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g., rheumatoid arthritis, psoriasis and fatty liver diseases) confer a realistic translational potential to these compounds, thus encouraging the investigation of highly selective agonists and antagonists of A3R. The present review summarizes information on the effect of latest-generation A3R ligands, not yet available in commerce, obtained by using different in vitro and in vivo models of various PNS- or CNS-related disorders. This review places particular focus on brain ischemia insults and colitis, where the prototypical A3R agonist, Cl-IB-MECA, and antagonist, MRS1523, have been used in research studies as reference compounds to explore the effects of latest-generation ligands on this receptor. The advantages and weaknesses of these compounds in terms of therapeutic potential are discussed. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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11 pages, 1312 KiB  
Review
The Purinergic Landscape of Type 2 Diabetes Mellitus
by Rocio Edith Garcia-Jacobo, Leticia Scussel Bergamin, Valentina Vultaggio-Poma, Maria Luiza Thorstenberg, Mario Tarantini, Mariana Haydee García-Hernández and Francesco Di Virgilio
Molecules 2022, 27(6), 1838; https://doi.org/10.3390/molecules27061838 - 11 Mar 2022
Cited by 4 | Viewed by 3121
Abstract
Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release [...] Read more.
Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic β-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic β-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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11 pages, 864 KiB  
Review
P2Y12 Purinergic Receptor and Brain Tumors: Implications on Glioma Microenvironment
by Fernanda Bueno Morrone, Pedro Vargas, Liliana Rockenbach and Thamiris Becker Scheffel
Molecules 2021, 26(20), 6146; https://doi.org/10.3390/molecules26206146 - 12 Oct 2021
Cited by 8 | Viewed by 2233
Abstract
Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor’s aggressiveness. In response to hypoxia and glioma therapy, the amounts of [...] Read more.
Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor’s aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides’ interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy. Full article
(This article belongs to the Special Issue Purinergic Signaling: Targeting GPCRs, Ion Channels and Enzymes—A Theme Issue in Honor of Dr. Kenneth A. Jacobson)
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