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1.
Antagonists of the adenosine receptors (A 1 and A 2A subtypes) are widely researched as potential drug candidates for their role in Parkinson’s disease-related cognitive deficits (A 1 subtype), motor dysfunction (A 2A subtype) and to exhibit neuroprotective properties (A 2A subtype). Previously the benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was found to display both A 1 and A 2A adenosine receptor affinity in the low micromolar range. Prompted by this, the α-pyrone core was structurally modified to explore related benzoxazinone and quinazolinone homologues previously unknown as adenosine receptor antagonists. Overall, the C2-substituted quinazolinone analogues displayed superior A 1 and A 2A adenosine receptor affinity over their C2-substituted benzoxazinone homologues. The benzoxazinones were devoid of A 2A adenosine receptor binding, with only two compounds displaying A 1 adenosine receptor affinity. In turn, the quinazolinones displayed varying degrees of affinity (low micromolar range) towards the A 1 and A 2A adenosine receptor subtypes. The highest A 1 adenosine receptor affinity and selectivity were favoured by methyl para-substitution of phenyl ring B (A 1Ki = 2.50 μM). On the other hand, 3,4-dimethoxy substitution of phenyl ring B afforded the best A 2A adenosine receptor binding (A 2AKi = 2.81 μM) among the quinazolinones investigated. In conclusion, the quinazolinones are ideal lead compounds for further structural optimization to gain improved adenosine receptor affinity, which may find therapeutic relevance in Parkinson’s disease-associated cognitive deficits and motor dysfunctions as well as exerting neuroprotective properties. 相似文献
2.
In situations of hypoxia, glutamate excitotoxicity induces neuronal death. The release of extracellular adenosine is also triggered and is accompanied by an increase of the stress mediator, corticotrophin‐releasing factor (CRF). Adenosine A 2A receptors contribute to glutamate excitoxicity and their blockade is effective in stress‐induced neuronal deficits, but the involvement of CRF on this effect was never explored. We now evaluated the interaction between A 2A and CRF receptors (CRFR) function, upon glutamate insult. Primary rat cortical neuronal cultures (9 days in vitro) expressing both CRF 1R and CRF 2R were challenged with glutamate (20–1000 μM, 24 h). CRF 1R was found to co‐localize with neuronal markers and CRF 2R to be present in both neuronal and glial cells. The effects of the CRF and A 2A receptors ligands on cell viability were measured using propidium iodide and Syto‐13 fluorescence staining. Glutamate decreased cell viability in a concentration‐dependent manner. Urocortin (10 pM), an agonist of CRF receptors, increased cell survival in the presence of glutamate. This neuroprotective effect was abolished by blocking either CRF 1R or CRF 2R with antalarmin (10 nM) or anti‐Sauvagine‐30 (10 nM), respectively. The blockade of A 2A receptors with a selective antagonist SCH 58261 (50 nM) improved cell viability against the glutamate insult. This effect was dependent on CRF 2R, but not on CRF 1R activation. Overall, these data show a protective role of CRF in cortical neurons, against glutamate‐induced death. The neuroprotection achieved by A 2A receptors blockade requires CRF 2R activation. This interaction between the adenosine and CRF receptors can explain the beneficial effects of using A 2A receptor antagonists against stress‐induced noxious effects. 相似文献
3.
Parkinson’s disease (PD) signs and symptoms regularly include tremor. Interestingly, the nucleoside guanosine (GUO) has already proven to be effective in reducing reserpine-induced tremulous jaw movements (TJMs) in rodent models, thus becoming a promising antiparkinsonian drug. Here, we aimed at revealing the mechanism behind GUO antiparkinsonian efficacy by assessing the role of adenosine A1 and A2A receptors (A1R and A2AR) on GUO-mediated anti-tremor effects in the reserpinized mouse model of PD. Reserpinized mice showed elevated reactive oxygen species (ROS) production and cellular membrane damage in striatal slices assessed ex vivo and GUO treatment reversed ROS production. Interestingly, while the simultaneous administration of sub-effective doses of GUO (5 mg/kg) and SCH58261 (0.01 mg/kg), an A2AR antagonist, precluded reserpine-induced TJMs, these were ineffective on reverting ROS production in ex vivo experiments. Importantly, GUO was able to reduce TJM and ROS production in reserpinized mouse lacking the A2AR, thus suggesting an A2AR-independent mechanism of GUO-mediated effects. Conversely, the administration of DPCPX (0.75 mg/kg), an A1R antagonist, completely abolished both GUO-mediated anti-tremor effects and blockade of ROS production. Overall, these results indicated that GUO anti-tremor and antioxidant effects in reserpinized mice were A1R dependent but A2AR independent, thus suggesting a differential participation of adenosine receptors in GUO-mediated effects. 相似文献
4.
The cross talk between different membrane receptors is the source of increasing research. We designed and synthesized a new hetero-bivalent ligand that has antagonist properties on both A 1 adenosine and μ opiate receptors with a Ki of 0.8 ± 0.05 and 0.7 ± 0.03 μM, respectively. This hybrid molecule increases cAMP production in cells that over express the μ receptor as well as those over expressing the A 1 adenosine receptor and reverses the antalgic effects of μ and A 1 adenosine receptor agonists in animals. 相似文献
5.
Adenosine A 1 and A 2A receptors are attracting great interest as drug targets for their role in cognitive and motor deficits, respectively. Antagonism of both these adenosine receptors may offer therapeutic benefits in complex neurological diseases, such as Alzheimer’s and Parkinson’s disease. The aim of this study was to explore the affinity and selectivity of 2-benzylidene-1-tetralone derivatives as adenosine A 1 and A 2A receptor antagonists. Several 5-hydroxy substituted 2-benzylidene-1-tetralone analogues with substituents on ring B were synthesized and assessed as antagonists of the adenosine A 1 and A 2A receptors via radioligand binding assays. The results indicated that hydroxy substitution in the meta and para position of phenyl ring B, displayed the highest selectivity and affinity for the adenosine A 1 receptor with K i values in the low micromolar range. Replacement of ring B with a 2-amino-pyrimidine moiety led to compound 12 with an increase of affinity and selectivity for the adenosine A 2A receptor. These substitution patterns led to enhanced adenosine A 1 and A 2A receptor binding affinity. The para-substituted 5-hydroxy analogue 3 behaved as an adenosine A 1 receptor antagonists in a GTP shift assay performed with rat whole brain membranes expressing adenosine A 1 receptors. In conclusion, compounds 3 and 12, showed the best adenosine A 1 and A 2A receptor affinity respectively, and therefore represent novel adenosine receptor antagonists that may have potential with further structural modifications as drug candidates for neurological disorders. 相似文献
6.
Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1- f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1- f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2- f]purine-2,4(1 H,3 H)-dione ( 21g, IC 50 human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A 1/A 2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2- f]purine-2,4(1 H,3 H)dione ( 19f, Ki, human receptors, A 1: 0.249 μM, A 2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2- f]purine-2,4(1 H,3 H)-dione ( 19g, Ki A 1: 0.605 μM, Ki A 2A: 0.417 μM, IC 50 MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo. 相似文献
7.
Cancer is a chronic disease and its pathogenesis is well correlated with infection and inflammation. Adenosine is a purine nucleoside, which is produced under metabolic stress like hypoxic conditions. Acute or chronic inflammatory conditions lead to the release of precursor adenine nucleotides (adenosine triphosphate (ATP), adenosien diphosphate (ADP) and adenosine monophosphate (AMP)) from cells, which are extracellularly catabolized into adenosine by extracellular ectonucleotidases, i.e., CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. It is now well-known that adenosine is secreted by cancer as well as immune cells during tumor pathogenesis under metabolic stress or hypoxia. Once adenosine is released into the extracellular environment, it exerts various immunomodulatory effects via adenosine receptors (A 1, A 2A, A 2B, and A 3) expressed on various immune cells (i.e., macrophages, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, dendritic cells (DCs), T cells, regulatory T cell (T regs), etc.), which play very important roles in the pathogenesis of cancer. This review is intended to summarize the role of inflammation and adenosine in the immunopathogenesis of tumor along with regulation of tumor-specific immune response and its modulation as an adjunct approach to tumor immunotherapy. 相似文献
8.
Adenosine, a purine nucleoside, acts as a regulatory molecule, by binding to specific G-protein-coupled A 1, A 2A, A 2B, and A 3 cell surface receptors. We have recently demonstrated that adenosine induces a differential effect on tumor and normal cells. While inhibiting in vitro tumor cell growth, it stimulates bone marrow cell proliferation. This dual activity was mediated through the A3 adenosine receptor. This study showed that a synthetic agonist to the A3 adenosine receptor, 2-chloro- N6-(3-iodobenzyl)-adenosine-5′- N-methyl-uronamide (Cl-IB-MECA), at nanomolar concentrations, inhibited tumor cell growth through a cytostatic pathway, i.e., induced an increase number of cells in the G0/G1 phase of the cell cycle and decreased the telomeric signal. Interestingly, Cl-IB-MECA stimulates murine bone marrow cell proliferation through the induction of granulocyte-colony-stimulating factor. Oral administration of Cl-IB-MECA to melanoma-bearing mice suppressed the development of melanoma lung metastases (60.8 ± 6.5% inhibition). In combination with cyclophosphamide, a synergistic anti-tumor effect was achieved (78.5 ± 9.1% inhibition). Furthermore, Cl-IB-MECA prevented the cyclophosphamide-induced myelotoxic effects by increasing the number of white blood cells and the percentage of neutrophils, demonstrating its efficacy as a chemoprotective agent. We conclude that A3 adenosine receptor agonist, Cl-IB-MECA, exhibits systemic anticancer and chemoprotective effects. 相似文献
9.
Inosine is an endogenous nucleoside that is produced by metabolic deamination of adenosine. Inosine is metabolically more stable (half-life 15 h) than adenosine (half-life < 10 s). Inosine exerts anti-inflammatory and immunomodulatory effects similar to those observed with adenosine. These effects are mediated in part through the adenosine A 2A receptor (A 2AR). Relative to adenosine inosine exhibits a lower affinity towards the A 2AR. Therefore, it is generally believed that inosine is incapable of activating the A 2AR through direct engagement, but indirectly activates the A 2AR upon metabolic conversion to higher affinity adenosine. A handful of studies, however, have provided evidence for direct inosine engagement at the A 2AR leading to activation of downstream signaling events and inhibition of cytokine production. Here, we demonstrate that under conditions devoid of adenosine, inosine as well as an analog of inosine 6-S-[(4-Nitrophenyl)methyl]-6-thioinosine selectively and dose-dependently activated A 2AR-mediated cAMP production and ERK1/2 phosphorylation in CHO cells stably expressing the human A 2AR. Inosine also inhibited LPS-stimulated TNF-α, CCL3 and CCL4 production by splenic monocytes in an A 2AR-dependent manner. In addition, we demonstrate that a positive allosteric modulator (PAM) of the A 2AR enhanced inosine-mediated cAMP production, ERK1/2 phosphorylation and inhibition of pro-inflammatory cytokine and chemokine production. The cumulative effects of allosteric enhancement of adenosine-mediated and inosine-mediated A 2AR activation may be the basis for the sustained anti-inflammatory and immunomodulatory effects observed in vivo and thereby provide insights into potential therapeutic interventions for inflammation- and immune-mediated diseases. 相似文献
10.
A series of 2-phenylethynyladenosine (PEAdo) derivatives substituted in the N 6- and 4′-position was synthesised and the new derivatives were tested at the four human adenosine receptors stably transfected into Chinese hamster ovary (CHO) cells, using radioligand binding studies (A 1, A 2A, A 3) or adenylyl cyclase activity assay (A 2B). Binding studies showed that the presence of a phenyl ethynyl group in the 2 position of adenosine favoured the interaction with A 3 receptors, resulting in compounds endowed with high affinity and selectivity for the A 3 subtype. Additional substitution of the N 6- and 4′-position increases both A 3 affinity and selectivity. The results showed that the new compounds have a good affinity for the A 3 receptor and in particular, the N 6-methoxy-2-phenylethynyl-5′-N-methylcarboxamidoadenosine, with a K i at A 3 of 1.9 nM and a selectivity A 1/A 3 and A 2A/A 3 of 4,800- and 8,600-fold, respectively. Therefore, it is one of the most potent and selective agonists at the human A 3 adenosine receptor subtype reported so far. Furthermore, functional assays of inhibition of 10 μM forskolin-stimulated cAMP production via the adenosine A 3 receptor revealed that the new trisubstituted adenosine derivatives behave as full agonist of this receptor subtype. Docking analysis of these compounds was performed at a homology model of the human A 3 receptor based on the bovine rhodopsin crystal structure as template, and the results are in accordance with the biological data.An erratum to this article can be found at 相似文献
11.
Adenosine can show anti-inflammatory as well as pro-inflammatory activities. The contribution of the specific adenosine receptor
subtypes in various cells, tissues and organs is complex. In this study, we examined the effect of the adenosine A 2A receptor agonist CGS 21680 and the A 2BR antagonist PSB-1115 on acute inflammation induced experimentally by 2,4,6-trinitrobenzenesulfonic acid (TNBS) on rat ileum/jejunum
preparations. Pre-incubation of the ileum/jejunum segments with TNBS for 30 min resulted in a concentration-dependent inhibition
of acetylcholine (ACh)-induced contractions. Pharmacological activation of the A 2AR with CGS 21680 (0.1–10 μM) pre-incubated simultaneously with TNBS (10 mM) prevented concentration-dependently the TNBS-induced
inhibition of the ACh contractions. Stimulation of A 2BR with the selective agonist BAY 60-6583 (10 μM) did neither result in an increase nor in a further decrease of ACh-induced
contractions compared to the TNBS-induced inhibition. The simultaneous pre-incubation of the ileum/jejunum segments with TNBS
(10 mM) and the selective A 2BR antagonist PSB-1115 (100 μM) inhibited the contraction-decreasing effect of TNBS. The effects of the A 2AR agonist and the A 2BR antagonist were in the same range as the effect induced by 1 μM methotrexate. The combination of the A 2AR agonist CGS 21680 and the A 2BR antagonist PSB-1115 at subthreshold concentrations of both agents found a significant amelioration of the TNBS-diminished
contractility. Our results demonstrate that the activation of A 2A receptors or the blockade of the A 2B receptors can prevent the inflammation-induced disturbance of the ACh-induced contraction in TNBS pre-treated small intestinal
preparations. The combination of both may be useful for the treatment of inflammatory bowel diseases. 相似文献
12.
Limonene is a major aromatic compound in essential oils extracted from citrus rind. The application of limonene, especially in aromatherapy, has expanded significantly, but its potential effects on cellular metabolism have been elusive. We found that limonene directly binds to the adenosine A 2A receptor, which may induce sedative effects. Results from an in vitro radioligand binding assay showed that limonene exhibits selective affinity to A 2A receptors. In addition, limonene increased cytosolic cAMP concentration and induced activation of protein kinase A and phosphorylation of cAMP-response element-binding protein in Chinese hamster ovary cells transfected with the human adenosine A 2A receptor gene. Limonene also increased cytosolic calcium concentration, which can be achieved by the activation of adenosine A 2A receptors. These findings suggest that limonene can act as a ligand and an agonist for adenosine A 2A receptors. 相似文献
13.
Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. Adenosine released from different
cells or generated through the activity of cell-surface ectoenzymes exerts its effects through the binding of four different
G-protein-coupled adenosine receptors. In platelets, binding of A 2 subtypes (A 2A or A 2B) leads to consequent elevation of intracellular cyclic adenosine monophosphate, an inhibitor of platelet activation. The
significance of this ligand and its receptors for platelet activation is addressed in this review, including how adenosine
metabolism and its A 2 subtype receptors impact the expression and activity of adenosine diphosphate receptors. The expression of A 2 adenosine receptors is induced by conditions such as oxidative stress, a hallmark of aging. The effect of adenosine receptors
on platelet activation during aging is also discussed, as well as potential therapeutic applications. 相似文献
14.
Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis. 相似文献
15.
The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A 2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the adenosine receptor (AR) binding affinities of the newly synthesized xanthines have also been studied. The compounds displayed moderate to potent binding affinities toward various adenosine receptor subtypes when evaluated through radioligand binding studies. However, most of the compounds showed the maximum affinity for the A 2A subtype, some with high selectivity versus all other subtypes. Xanthine carboxylate amide 13b with a diethylaminoethylamino moiety at the para-position of the 8-phenylxanthine scaffold was identified as the most potent A 2A adenosine receptor ligand with Ki = 0.06 μM. Similarly potent and highly A 2A-selective are the isovanillin derivatives 16a and 16d. In addition, the newly synthesized xanthine derivatives showed good in vivo bronchospasmolytic activity when tested in guinea pigs. 相似文献
16.
Resveratrol, a natural polyphenolic compound, has been studied as a neuroprotective molecule. Our group has demonstrated that such effect is closely associated with modulation of glial functionality, but the underlying mechanisms are not fully understood. Because astrocytes actively participate in the brain inflammatory response, and activation of adenosine receptors can attenuate inflammatory processes, the aim of this study was to investigate the role of adenosine receptors as a mechanism for resveratrol glioprotection, particularly regarding to neuroinflammation. Therefore, primary astrocyte cultures were co-incubated with resveratrol and selective antagonists of A 1, A 2A, and A 3 adenosine receptors, as well as with caffeine (a non-selective adenosine receptor antagonist), and then challenged with bacterial inflammogen lipopolysaccharide (LPS). Caffeine and selective adenosine receptor antagonists abolished the anti-inflammatory effect of resveratrol. In accordance with these effects, resveratrol prevented LPS-induced decrease in mRNA levels of adenosine receptors. Resveratrol could also prevent the activation of pro-inflammatory signaling pathways, such as nuclear factor κB (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in a mechanism dependent on adenosine receptors. Conversely, trophic factors and protective signaling pathways, including sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and phosphoinositide 3-kinase (PI3K)/Akt were positively modulated by resveratrol in both LPS-stimulated and unstimulated astrocytes, but adenosine receptor antagonism did not abrogate all effects of resveratrol. To our knowledge, our data provide the first evidence that adenosine receptors are involved in the anti-inflammatory activity of resveratrol in astrocytes, thus exerting an important role for resveratrol-mediated glioprotection. 相似文献
17.
Intraocular pressure is directly dependent on aqueous humor flow into, and resistance to flow out of, the eye. Adenosine has complex effects on intraocular pressure. Stimulation of A 1 and A 2A adenosine receptors changes intraocular pressure oppositely, likely through opposing actions on the outflow of aqueous humor. While the cellular sites regulating outflow resistance are unknown, the cells lining the inner wall of Schlemm's canal (SC) are a likely regulatory site. We applied selective adenosine receptor agonists to SC cells in vitro to compare the responses to A 1 and A 2A stimulation. Parallel studies were conducted with human inner-wall SC cells isolated by a novel enzyme-assisted technique and with cannula-derived mixed inner- and outer-wall SC cells. A 1 agonists increased whole cell currents of both inner-wall and cannula-derived SC cells. An A 2A agonist reduced currents most consistently in specifically inner-wall SC cells. Those currents were also increased by A 2B, but not consistently affected by A 3, stimulation. A 1, A 2A, and A 3 agonists all increased SC-cell intracellular Ca 2+. The electrophysiological results are consistent with the possibility that inner-wall SC cells may mediate the previously reported modulatory effects of adenosine on outflow resistance. The results are also consistent with the presence of functional A 2B, as well as A 1, A 2A, and A 3 adenosine receptors in SC cells. intraocular pressure; aqueous humor outflow; ion transport; adenosine agonists 相似文献
18.
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named
A 1, A 2A, A 2B and A 3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A 2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding
of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A 2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective
agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview
of the recent advancements in identifying potent and selective A 2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine
ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N
6-, C 2-positions of the purine heterocycle and/or at the 5′-position of the ribose moiety or combinations of these substitutions.
Compounds 1-deoxy-1-{6-[ N′-(furan-2-carbonyl)-hydrazino]-9 H-purin-9-yl}-N-ethyl- β-D-ribofuranuronamide ( 19, hA 1
K
i = 1050 nM, hA 2A
K
i = 1550 nM, hA 2B EC 50 = 82 nM, hA 3
K
i > 5 μM) and its 2-chloro analogue 23 (hA 1
K
i = 3500 nM, hA 2A
K
i = 4950 nM, hA 2B EC 50 = 210 nM, hA 3
K
i > 5 μM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay
in Chinese hamster ovary (CHO) cells expressing hA 2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide
( BAY-60–6583, hA 1, hA 2A, hA 3 EC 50 > 10 μM; hA 2B EC 50 = 3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis. 相似文献
19.
The effects of adenosine and several structural analogues of adenosine upon thymidine incorporation into human tumour cells and rat cervical lymphocytes were investigated. The analogue NECA, which has equal specificity for the A 1 and A 2 receptor, had the most inhibitory effect on lymphocyte proliferation while the A 1 agonists had limited effects, suggesting that these cells possess principally A 2 adenosine receptors. In the case of human tumour cells, however, the most inhibitory effect on proliferation was obtained with the A 1-specific analogues. The general order of inhibitory effects of adenosine analogues on thymidine incorporation in human tumour cells was: S-ENBA>CPA=R-PIA>S-PIA>NECA. These findings suggest that in the cells presently studied the A 1 adenosine receptor predominates. Removal of exogenous adenosine by growth in the presence of adenosine deaminase inhibited thymidine incorporation. The effect of adenosine removal lends further support to the proposal that adenosine has some, as yet unidentified, regulatory role in the control of human tumour cell proliferation. © 1997 John Wiley & Sons, Ltd. 相似文献
20.
Hyperhomocysteinemia is associated with coronary artery disease (CAD). The mechanistic aspects of this relationship are unclear. In CAD patients, homocysteine (HCy) concentration correlates with plasma level of adenosine that controls the coronary circulation via the activation of adenosine A 2A receptors (A 2AR). We addressed in CAD patients the relationship between HCy and A 2AR production, and in cellulo the effect of HCy on A 2AR function. 46 patients with CAD and 20 control healthy subjects were included. We evaluated A 2AR production by peripheral blood mononuclear cells using Western blotting. We studied in cellulo (CEM human T cells) the effect of HCy on A 2A R production as well as on basal and stimulated cAMP production following A 2A R activation by an agonist‐like monoclonal antibody. HCy concentration was higher in CAD patients vs controls (median, range: 16.6 [7‐45] vs 8 [5‐12] µM, P < 0.001). A 2A R production was lower in patients vs controls (1.1[0.62‐1.6] vs 1.53[0.7‐1.9] arbitrary units, P < 0.001). We observed a negative correlation between HCy concentration and A 2A R production ( r = ?0.43; P < 0.0001), with decreased A 2A R production above 25 µM HCy. In cellulo, HCy inhibited A 2AR production, as well as basal and stimulated cAMP production. In conclusion, HCy is negatively associated with A 2A R production in CAD patients, as well as with A 2A R and cAMP production in cellulo. The decrease in A 2A R production and function, which is known to hamper coronary blood flow and promote inflammation, may support CAD pathogenesis. 相似文献
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