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 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 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 Different Serotonin Receptor Agonists Have Distinct Effects on Sound-Evoked Responses in Inferior Colliculus

2006 ◽  
Vol 96 (5) ◽  
pp. 2177-2188 ◽  
Author(s):  
Laura M. Hurley
Keyword(s):  
Inferior Colliculus ◽  
Auditory Processing ◽  
Serotonin Receptors ◽  
Serotonin Receptor ◽  
Frequency Tuning ◽  
Receptor Subtypes ◽  
Tuning Curves ◽  
Wide Range ◽  
Selective Agonists ◽  
Auditory Nucleus

The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing.

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.

scholarly journals Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Siew Lee Cheong ◽  
Gopalakrishnan Venkatesan ◽  
Priyankar Paira ◽  
Ramasamy Jothibasu ◽  
Alexander Laurence Mandel ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Rational Design ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Design And Optimization ◽  
The Past ◽  
Chemistry Research ◽  
Pathological Conditions ◽  
Structure Activity ◽  
Selective Antagonists

In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3) has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR) profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

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.

Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes

2006 ◽  
Vol 291 (4) ◽  
pp. H1875-H1882 ◽  
Author(s):  
R. Ray Morrison ◽  
Bunyen Teng ◽  
Peter J. Oldenburg ◽  
Laxmansa C. Katwa ◽  
Jurgen B. Schnermann ◽  
...  
Keyword(s):  
Real Time ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Diastolic Pressure ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Receptor Subtypes ◽  
Rt Pcr ◽  
Targeted Deletion ◽  
Developed Pressure

To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A1AR deletion and/or ischemia-reperfusion. A1KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A1AR deletion. After 20 min of ischemia, CF was attenuated in A1KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A1KO hearts (54.4 ± 5.1 vs. WT 81.1 ± 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Postischemic efflux of LDH was greater in A1KO compared with WT hearts. Real-time RT-PCR demonstrated the absence of A1AR transcript in A1KO hearts, and the message for A2A, A2B, and A3 adenosine receptors was similar in uninstrumented A1KO and WT hearts. Ischemia-reperfusion increased A2B mRNA expression 2.5-fold in both WT and A1KO hearts without changing A1 or A3 expression. In WT hearts, ischemia transiently doubled A2A mRNA, which returned to preischemic level upon reperfusion, a pattern not observed in A1KO hearts. Together, these data affirm the cardioprotective role of A1ARs and suggest that induced expression of other adenosine receptor subtypes may participate in the response to ischemia-reperfusion in isolated murine hearts.

Recent Progress of Adenosine Receptor Modulators in the Development of Anticancer Chemotherapeutic Agents

2019 ◽  
Vol 25 (26) ◽  
pp. 2842-2858 ◽  
Author(s):  
Sarapynbiang Marwein ◽  
Bijayashree Mishra ◽  
Utpal C. De ◽  
Pratap C. Acharya
Keyword(s):  
Anticancer Agents ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Metastatic Tumor ◽  
Chemotherapeutic Agents ◽  
Effective Management ◽  
Antitumor Property ◽  
Important Target ◽  
Receptor Modulators

Increased risks of peripheral toxicity and undesired adverse effects associated with chemotherapeutic agents are the major medical hurdles in cancer treatment that worsen the quality of life of cancer patients. Although several novel and target-specific anticancer agents have been discovered in the recent past, none of them have proved to be effective in the management of metastatic tumor. Therefore, there is a continuous effort for the discovery of safer and effective cancer chemotherapeutic agent. Adenosine receptors have been identified as an important target to combat cancer because of their inherent role in the antitumor process. The antitumor property of the adenosine receptor is primarily attributed to their inherited immune response against the tumors. These findings have opened a new chapter in the anticancer drug discovery through adenosine receptor-mediated immunomodulation. This review broadly outlines the biological mechanism of adenosine receptors in mediating the selective cytotoxicity as well as the discovery of various classes of adenosine receptor modulators in the effective management of solid tumors.

scholarly journals Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts

2010 ◽  
Vol 299 (4) ◽  
pp. H1262-H1264 ◽  
Author(s):  
Carmen Methner ◽  
Katharina Schmidt ◽  
Michael V. Cohen ◽  
James M. Downey ◽  
Thomas Krieg
Keyword(s):  
Infarct Size ◽  
Knockout Mice ◽  
Adenosine Receptors ◽  
Coronary Occlusion ◽  
Ischemic Postconditioning ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Cgs 21680 ◽  
Selective Agonists

Pre- and postconditioning depend on the activation of adenosine receptors (ARs) at the end of the index ischemia. The aim of this study was to determine which receptor subtypes must be activated. In situ mouse hearts underwent 30 min of regional ischemia, followed by 2 h of reperfusion. As expected, either ischemic postconditioning (6 cycles of 10 s of reperfusion and 10 s of coronary occlusion) or infusion of the selective A2b adenosine receptor (A2bAR) agonist BAY60-6583 (BAY60) for 60 min, starting 5 min before reperfusion reduced infarct size in wild-type C57Bl/6N mice. Protection from either was abolished by the selective A2bAR antagonist MRS-1754, confirming a role for A2bAR. Additionally, the coadministration of ischemic postconditioning and a selective A2aAR antagonist led to the loss of protection as well. 5′-Ectonucleotidase (CD73) is thought to be necessary for the production of adenosine during ischemia. As predicted, ischemic postconditioning did not protect CD73 knockout mice. Selective agonists of either A2bAR (BAY60) or A2aAR (CGS-21680), as well as the coadministration of ischemic postconditioning and BAY60, also failed to protect hearts of the CD73 knockout mice. But the nonselective A1/A2AR agonist 5′-( N-ethylcarboxamido)adenosine (NECA) was protective, suggesting that the activation of multiple AR subtypes might be required. The coadministration of CGS-21680 and BAY60 also elicited profound protection, indicating that two AR subtypes, A2a and A2b, must be simultaneously activated for protection to occur.

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