scholarly journals Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy

2019 ◽  
Vol 20 (21) ◽  
pp. 5475 ◽  
Author(s):  
Nina Wolska ◽  
Marcin Rozalski
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Purinergic Receptor ◽  
Blood Platelets ◽  
Blood Platelet ◽  
Intracellular Camp ◽  
Receptor Subtypes ◽  
Adenosine Receptor Agonists ◽  
Anti Platelet Therapy ◽  
G Protein Coupled

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function.

scholarly journals Molecular probes for the human adenosine receptors

2020 ◽  
Author(s):  
Xue Yang ◽  
Laura H. Heitman ◽  
Adriaan P. IJzerman ◽  
Daan van der Es
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Molecular Probes ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
The Past ◽  
New Chemical Entities ◽  
And Function ◽  
Receptor Modulators ◽  
G Protein Coupled

AbstractAdenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail.

scholarly journals Adenosine Receptors as Targets for Therapeutic Intervention

2014 ◽  
Vol 11 (1) ◽  
pp. 96-101 ◽  
Author(s):  
B Suvarna
Keyword(s):  
Medical Journal ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Receptor Subtypes ◽  
Therapeutic Application ◽  
Chemistry Research ◽  
Wide Range ◽  
The World ◽  
Selective Agonists ◽  
Receptor Modulators

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer. DOI: http://dx.doi.org/10.3126/kumj.v11i1.11054 Kathmandu University Medical Journal Vol.11(1) 2013: 96-101

scholarly journals Regulation of Adenosine Receptor Subtypes during Cultivation of Human Monocytes: Role of Receptors in Preventing Lipopolysaccharide-Triggered Respiratory Burst

2004 ◽  
Vol 72 (3) ◽  
pp. 1349-1357 ◽  
Author(s):  
Andrea Thiele ◽  
Romy Kronstein ◽  
Anne Wetzel ◽  
Anja Gerth ◽  
Karen Nieber ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Receptor Agonist ◽  
Inhibitory Action ◽  
Suppressive Effect ◽  
Receptor Subtypes ◽  
Human Monocytes ◽  
Oxygen Intermediates ◽  
Adenosine Concentration

ABSTRACT Adenosine is a potent anti-inflammatory agent that modulates the function of cells involved in the inflammatory response. Here we show that it inhibits lipopolysaccharide (LPS)-induced formation of reactive oxygen intermediates (ROI) in both freshly isolated and cultured human monocytes. Blocking of adenosine uptake and inactivation of the adenosine-degrading enzyme adenosine deaminase enhanced the inhibitory action of adenosine, indicating that both pathways regulate the extracellular adenosine concentration. Adenosine-mediated inhibition could be reversed by XAC (xanthine amine congener), an antagonist of the adenosine receptor A2A, and MRS 1220 {N-9-chloro-2-(2-furanyl)[1, 2, 4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide}, an A3 receptor antagonist, in both cell populations, while DPCPX (1,3-dipropyl-8-cyclopentylxanthine), an A1 receptor antagonist, had no effect. Similar to what was seen with adenosine, CGS 21680, an A2A and A3 receptor agonist, and IB-MECA, a nonselective A1 and A3 receptor agonist, dose dependently prevented ROI formation, indicating the involvement of A3 and probably also A2A in the suppressive effect of adenosine. Pretreatment of monocytes with adenosine did not lead to changes in the LPS-induced increase in intracellular calcium levels ([Ca2+]i). Thus, participation of [Ca2+]i in the action of adenosine seems unlikely. The adenosine-mediated suppression of ROI production was found to be more pronounced when monocytes were cultured for 18 h, a time point at which changes in the mRNA expression of adenosine receptors were observed. Most prominent was the increase in the A2A receptor mRNA. These data demonstrate that cultivation of monocytes is accompanied by changes in the inhibitory action of adenosine mediated by A3 and probably also the A2A receptor and that regulation of adenosine receptors is an integral part of the monocyte differentiation program.

Regulation of Platelet Function By Adenosine Receptors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2348-2348
Author(s):  
Daniel N. Darlington ◽  
Xiaowu Wu ◽  
Kevin L. Chang ◽  
James Bynum ◽  
Andrew P. Cap
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Adenosine Diphosphate ◽  
Severe Trauma ◽  
Intracellular Camp ◽  
Platelet Dysfunction ◽  
Cgs 21680 ◽  
Adenosine Agonist ◽  
A2a Receptor

Introduction: We have recently shown that severe trauma and hemorrhage lead to inhibition of platelet aggregation and an elevation in cyclic adenosine monophosphate (cAMP). Adenosine is one of the few humoral agents known to stimulate cAMP in platelets. Because adenosine is released from damaged tissue, it may contribute to the platelet dysfunction seen after severe trauma. Platelets have four adenosine receptors (A1, A2a, A2b and A3). These receptors are G-Protein Coupled Receptors and have been proposed to stimulate adenylyl cyclase and increase intracellular cAMP. Although studies have shown that stimulate A2a can inhibit platelet aggregation and elevate cAMP, there is little data elucidating the function of the other receptors. Objective: Define which adenosine receptors affects platelet aggregation and cAMP production. Methods: Platelet-rich plasma (PRP) was isolated from whole blood of human volunteers, and centrifuged at 200g for 10min. Light transmission aggregometry was performed using a plate reader (Synergy Neo2 Multimode Reader, BioTek) with constant agitation. PRP was stimulated with adenosine diphosphate (ADP) with or without various adenosine agonists or antagonists, including the non-metabolizable adenosine agonist 5-(N-ethyl-carboxamido) adenosine (NECA), antagonists to receptors A1 (DPCPX), A2a (Sch 58261), A2b (GS 6201) and A3 (MRS 1220), or agonists for A2a (CGS 21680) A2b (BAY 60-6583) or agonist A1 (CCPA), A2a (CGS 21680), A2b (Bay 60-6583), A3 (2-Cl-IB-Meca). Cyclic AMP was extracted from 100ul of PRP after adding 1ml of EtOH, 10mM ammonium formate, with 10ug/ml cGMP-Br as an internal control. Samples were centrifuged at 20K g for 10min, and supernatant dried. Samples were brought up in 200ul of 0.1% formic acid for analysis by Reverse Phase liquid chromatography/ Tandem Mass Spectroscopy (Quantiva, ThrermoFisher). N-8/group. Results: Adenosine diphosphate (100uM) leads to platelet aggregation (change in mAbsorbance units, Table 1). The adenosine agonist NECA inhibited aggregation to ADP and elevated cAMP in a dose dependent manner (pg/ml per 1000 plt, Table 1). Platelet aggregation was inhibited and cAMP was elevated after stimulation with agonists for adenosine receptor A2a agonist, but not A1, A2b, or A3 (Table 2). Antagonists for A2a, but not A1, A2b, A3, blocked NECA inhibition of ADP aggregation (Table 3). Agonist for adenosine receptor A2a inhibited the ADP-induced aggregation and elevated cAMP in a dose response manner (Table 4). Discussion: Adenosine inhibits platelet aggregation to ADP. The mechanism appears to be due to elevation in intracellular cAMP, and works through the A2a receptor. These data suggest that the A2a receptor could be potential target for a resuscitation strategy that could attenuate or prevent platelet dysfunction after trauma by preventing stimulation of adenylate cyclase and synthesis of cAMP. This study was funded by the US Army medical Research and Development Command. Disclosures No relevant conflicts of interest to declare.

scholarly journals Chemical Probes for the Adenosine Receptors

2019 ◽  
Vol 12 (4) ◽  
pp. 168 ◽  
Author(s):  
Stephanie Federico ◽  
Lucia Lassiani ◽  
Giampiero Spalluto
Keyword(s):  
Adenosine Receptors ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Subtypes ◽  
Chemical Probes ◽  
New Techniques ◽  
Compound Screening ◽  
New Applications ◽  
Covalent Ligands ◽  
G Protein Coupled

Research on the adenosine receptors has been supported by the continuous discovery of new chemical probes characterized by more and more affinity and selectivity for the single adenosine receptor subtypes (A1, A2A, A2B and A3 adenosine receptors). Furthermore, the development of new techniques for the detection of G protein-coupled receptors (GPCR) requires new specific probes. In fact, if in the past radioligands were the most important GPCR probes for detection, compound screening and diagnostic purposes, nowadays, increasing importance is given to fluorescent and covalent ligands. In fact, advances in techniques such as fluorescence resonance energy transfer (FRET) and fluorescent polarization, as well as new applications in flow cytometry and different fluorescence-based microscopic techniques, are at the origin of the extensive research of new fluorescent ligands for these receptors. The resurgence of covalent ligands is due in part to a change in the common thinking in the medicinal chemistry community that a covalent drug is necessarily more toxic than a reversible one, and in part to the useful application of covalent ligands in GPCR structural biology. In this review, an updated collection of available chemical probes targeting adenosine receptors is reported.

scholarly journals Caffeine accelerates recovery from general anesthesia via multiple pathways

2017 ◽  
Vol 118 (3) ◽  
pp. 1591-1597 ◽  
Author(s):  
Robert Fong ◽  
Suhail Khokhar ◽  
Atif N. Chowdhury ◽  
Kelvin G Xie ◽  
Josiah Hiu-Yuen Wong ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Intracellular Camp ◽  
Receptor Blockade ◽  
Adult Rats ◽  
Adenosine Receptor Antagonist ◽  
Recovery From Anesthesia ◽  
High Level ◽  
Camp Levels

Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i)-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine’s ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response. NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients “wake” when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia.

scholarly journals Discovery of benzothiazolylquinoline conjugates as novel human A 3 receptor antagonists: biological evaluations and molecular docking studies

2018 ◽  
Vol 5 (2) ◽  
pp. 171622 ◽  
Author(s):  
Bidisha Sarkar ◽  
Santanu Maiti ◽  
Gajanan Raosaheb Jadhav ◽  
Priyankar Paira
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Radioligand Binding ◽  
Physiological Responses ◽  
Docking Studies ◽  
Receptor Subtypes ◽  
Binding Data ◽  
Major Interest

Adenosine is known as an endogenous purine nucleoside and it modulates a wide variety of physiological responses by interacting with adenosine receptors. Among the four adenosine receptor subtypes, the A 3 receptor is of major interest in this study as it is overexpressed in some cancer cell lines. Herein, we have highlighted the strategy of designing the h A 3 receptor targeted novel benzothiazolylquinoline scaffolds. The radioligand binding data of the reported compounds are rationalized with the molecular docking results. Compound 6a showed best potency and selectivity at h A 3 among other adenosine receptors.

Pharmacological probes for A1 and A2 adenosine receptors in vivo in feline pulmonary vascular bed

1996 ◽  
Vol 270 (2) ◽  
pp. H610-H619 ◽  
Author(s):  
C. F. Neely ◽  
I. Matot
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Pulmonary Vasculature ◽  
In Vivo Model ◽  
Edema Formation ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
Cgs 21680 ◽  
A2 Adenosine Receptors

Under conditions of controlled pulmonary blood flow and constant left atrial pressure, adenosine produces dose-dependent, tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. The potency profile for adenosine receptor agonists to produce vasoconstriction at low baseline PV tone is 5'-(N-ethylcarboxamido)adenosine > or = CGS-21680 > or = 2-chloroadenosine (2-CADO) > or = [R]-N6-(2-phenylisopropyl)adenosine (R-PIA) > or = N6-cyclopentyladenosine > adenosine > > CV-1808. After an increase in PV tone with the use of an intralobar infusion of the thromboxane mimic U-46619, the potency profile for adenosine receptor agonists to produce vasodilation at elevated PV tone is 2-CADO > or = CV-1808 > or = CGS-21680 > R-PIA > or = adenosine. The selective A1 adenosine receptor antagonists xanthine amine congener (XAC) and 8-cyclopentyl-1,3-dipropylxanthine (DP-CPX) significantly antagonize the vasoconstrictor responses of adenosine and R-PIA at low baseline PV tone while having less effect on the vasodilator responses of adenosine, 2-CADO, and R-PIA at elevated PV tone. DPCPX antagonizes the vasoconstrictor responses of CGS-21680 at low baseline PV tone. The nonselective A1 and A2 adenosine receptor antagonist BWA-1433U significantly antagonizes vasoconstrictor responses of R-PIA and vasodilator responses of adenosine, 2-CADO, and R-PIA. These data support that adenosine produces vasoconstriction at low baseline PV tone and vasodilation at elevated PV tone in the feline PV bed by acting on A1 and A2 adenosine receptors, respectively. Compared with the adenosine receptor agonists tested in this in vivo model, R-PIA and CV-1808 are the most selective adenosine receptor agonists for A1 and A2 adenosine receptors, respectively, in the feline PV bed. R-PIA, CV-1808, DPCPX, and XAC may be used in this in vivo model to define the roles of A1 and A2 adenosine receptors in acute lung injury and pathophysiological changes in the pulmonary vasculature associated with pulmonary hypertension and edema formation in the same animal model.

Sign in / Sign up

Export Citation Format

Share Document