Adenosine receptors as therapeutic targets

Jacobson, Kenneth A.; Gao, Zhan‐Guo

doi:10.1038/nrd1983

Cited by 1,255 publications

(1,391 citation statements)

References 199 publications

(221 reference statements)

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“…Therefore, during a prolonged severe OGD insult, the roles of A 1 and A 3 receptors drastically diverge. On the whole, the data support the wellestablished neuroprotective role of A 1 receptors [9,12,41] and confirm an opposite, deleterious, role of A 3 receptors during prolonged ischemia [14].…”

Section: Discussionsupporting

confidence: 75%

“…The expression of A 3 receptors in the brain is lower than that of other adenosine receptor subtypes [6], and the affinity for adenosine, calculated from binding experiments in rat brain membranes (6.5 μM [2]), is lower than that of A 1 [7] and A 2A [8] receptors. However, during ischemic conditions in vivo [9] and in vitro [10] adenosine extracellular concentrations may be sufficiently high to activate adenosine A 3 receptors, which may play a role in brain ischemia (see [11,12]). …”

Section: Introductionmentioning

confidence: 99%

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Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Pugliese

Coppi

Volpini

et al. 2007

Biochemical Pharmacology

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The role of adenosine A 3 receptors in synaptic transmission under severe (7 min) and shorter (2-5 min) ischemic conditions, obtained by oxygen and glucose deprivation (OGD), was investigated in rat hippocampal slices. The effects of selective A 3 agonists or antagonists were examined on field excitatory postsynaptic potentials (fEPSPs) extracellularly recorded at the dendritic level of the CA1 pyramidal region. The novel, selective A 3 antagonist LJ1251 ((2R,3R,4S)-2-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)tetrahydrothiophene-3,4-diol, 0.1-10 nM) protected hippocampal slices from irreversible fEPSP depression induced by severe OGD and prevented or delayed the appearance of anoxic depolarization. Similar results were obtained when severe OGD was carried out with a long, receptor-desensitizing exposure to various selective A 3 agonists: 5′-Nmethylcarboxamidoadenosine derivatives Cl-IB-MECA (N 6 -(3-iodobenzyl)-2-chloro), VT72 (N 6 -methoxy-2-phenylethynyl), VT158 (N 6 -methoxy-2-phenylethynyl), VT160 (N 6 -methoxy-2-(2-pyridinyl)-ethynyl), and VT163 (N 6 -methoxy-2-p-acetylphenylethynyl) and AR132 (N 6 -methyl-2-phenylethynyladenosine).The selective A 3 antagonist MRS1523 (3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridine carboxylate, 100 nM) reduced fEPSP depression evoked by 2-min OGD and induced a faster recovery of fEPSP amplitude after 5-min OGD. Similar results were obtained for 2-or 5-min OGD applied in the presence of each of the A 3 agonists tested. Shorter exposure to A 3 agonists significantly delayed the recovery of fEPSP amplitude after 5-min OGD.This indicates that A 3 receptors, stimulated by selective A 3 agonists, undergo desensitization during OGD. It is inferred that CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia (2 and 5 min) might exert A 1 -like protective effects on neurotransmission. Severe ischemia would transform the A 3 receptor-mediated effects from protective to injurious.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Pugliese

Coppi

Volpini

et al. 2007

Biochemical Pharmacology

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“…Thus, adenosine controls many brain functions in physiological and pathophysiological conditions (Fredholm et al, 2005a;Fredholm et al, 2005b) and has potent anticonvulsant (Boison, 2005;Dragunow, 1986;Dunwiddie, 1999) and neuroprotective (Cunha, 2005;Dragunow and Faull, 1988;Ribeiro, 2005) properties. Due to these properties of adenosine, an adenosinebased pharmacopoeia has been established for a variety of conditions (Jacobson and Gao, 2006) including the development of adenosine-based cell therapies for the treatment of focal epilepsies (Boison, 2007a;2007b).…”

Section: Neuromodulation By Adenosinementioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

200

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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“…13 Cardioprotection by selective A 3 AR agonists has been extensively explored in various species. [14][15][16] Other selective A 3 AR agonists have recently been reported, based on introduction of large substituents at the N 6 and C2 positions and modification of the ribose ring, particularly at the 4′ and 5′ positions.…”

mentioning

confidence: 99%

“…Binding assays were carried out using standard radioligands in Chinese hamster ovary (CHO) cells expressing the human A 1 The binding affinity at the mouse and rat A 3 ARs of the N 6 -methyl derivative 3 was considerably weaker than at the human A 3 AR (Table 1). Thus, this compound was balanced in affinity at mouse A 1 /A 3 ARs, with high selectivity in comparison to the mouse A2AAR.…”

mentioning

confidence: 99%

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

Melman

Gao

Kumar

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Abstract2-Chloro-5′ -N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo [3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A 3 adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A 1 AR. Therefore, we varied substituents at the N 6 and C2 positions in search of compounds that have improved A 3 AR selectivity and are species independent. An N 6 -methyl analogue was balanced in affinity at mouse A 1 /A 3 ARs, with high selectivity in comparison to the A 2A AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A 3 AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A 3 AR selectivity more effectively than similar chains attached at the 3 position of the N 6 -benzyl group. Keywordsnucleoside; G protein-coupled receptor; mouse; adenosine receptor; radioligand binding Adenosine is a protective mediator that has been described as a general endogenous signal for tissue protection and regeneration and even "the signal of life". 1,2 Adenosine activates four different receptor subtypes -A 1 , A 2A , A 2B , and A 3 -which are widely but differentially distributed throughout the body. 3 The A 3 adenosine receptor (AR) is located in some neurons, astrocytes, various immune cell populations (neutrophils, eosinophils, mast cells) and potentially muscle cells and endothelial cells. 4-7 The A 3 AR is coupled to inhibition of adenylate cyclase and also activates Akt and calcium mobilization. 8,9 Two potent and selective agonists of the A 3 AR, IB-MECA 1a and Cl-IB-MECA 1b, are currently in Phase II clinical trials for the treatment of rheumatoid arthritis, several other autoimmune inflammatory diseases, and cancer. 10-12 Protective mechanisms in the envisioned disease applications of A 3 AR agonists appear to be a downregulation of the NF-κB system, common to both arthritis and cancer treatments, 12 and a widespread correction of gene dysregulation induced in an Corresponding author: Dr. K.A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: 301-496-9024. Fax: 301-480-8422; Email: kajacobs@helix.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. .0]hexane) nucleoside analogues were used to determine that the biologically active conformat...

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Adenosine receptors as therapeutic targets

Cited by 1,255 publications

References 199 publications

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

The adenosine kinase hypothesis of epileptogenesis

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

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