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1.
Abstract A variety of adenosine analogues have been recently evaluated in order Lo find more potent and selective agonists on adenosine receptors. The most potent adenosine analogues acting on A 1 receptor, a high affinity receptor inhibitory to adenylate cyclase, are N 6-substituted compounds. So 6-cyclohexyladenosine (CHA) and 6-L-phenylisopropyladenosine (L-PIA) are extremely potent agonists on A 2 receptor, whereas they are relatively weak agonists on A receptor, a lower affinity receptor which is stirnulatory to cyclase, and they have no effect on the adenosine P site. 相似文献
2.
Abstract Adenosine derivatives bearing in 2-position the ( R, S)- phenylhydroxypropynyl chain were evaluated for their potency at human A 2B adenosine receptor, stably transfected on CHO cells, on the basis that ( R, S)-2-phenylhydroxy-propynyl-5′-N-ethylcarboxyamidoadenosine [( R, S)-PHPNECA] was found to be a good agonist at the A 2B receptor subtype. Biological studies demonstrated that the presence of small alkyl groups in N 6-position of these molecules are well tolerated, whereas large groups abolished A 2B potency. On the other hand, the presence of an ethyl group in the 4′-carboxamido function seems to be optimal, the ( S)-PHPNECA resulting the most potent agonist at A 2B receptor reported so far. 相似文献
3.
Abstract Synthesis of 2′-deoxy-2′-fluoro- N 6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A 3 adenosine receptor are described. 相似文献
4.
Abstract: Previous work from this laboratory has shown that retinal adenosine A 2 binding sites are localized over outer and inner segments of photoreceptors in rabbit and mouse retinal sections. In the present study, adenosine receptor binding has been characterized and localized in membranes from bovine rod outer segments (ROS). Saturation studies with varying concentrations (10–150 n M) of 5′-( N-[2,8- 3H]ethylcarboxamido)adenosine ([ 3H]NECA) and 100 μg of ROS membrane protein show a single site with a KD of 103 n M and a Bmax of 1.3 p M/mg of protein. Cold Scatchards, which used nonradiolabeled NECA (concentrations ranging from 10 n M to 250 n M) in competition with a fixed amount of [ 3H]NECA (30 n M), demonstrated the presence of a low-affinity site ( KD, 50 μ M) in addition to the high-affinity site. To confirm the presence of A 2abinding sites, saturation analyses with 2-p-(2-[ 3H]-carboxyethyl)phenylamino-5′- N-ethylcarboxamido adenosine (0–80 n M) also revealed a single population of high-affinity A 2a receptors ( KD, 9.4 n M). The binding sites labeled by [ 3H]NECA appear to be A 2 receptor sites because binding was displaced by increasing concentrations of 5′-( N-methylcarboxamido)adenosine and 2-chloroadenosine. ROS were fractionated into plasma and disk membranes for localization studies. Receptor binding assays, used to determine specific binding, showed that the greatest concentration of A 2 receptors was on the plasma membranes. Therefore, adenosine A 2 receptors are in a position to respond to changes in the concentration of extracellular adenosine, which may exhibit a circadian rhythm. 相似文献
5.
On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A 3 adenosine receptor, its 4′-thioadenosine derivatives were efficiently synthesized starting from D-gulonic γ -lactone. Among compounds tested, 2-chloro- N 6-(3-iodobenzyl)- and 2-chloro- N 6-methyl-4′ -thioadenosine-5′ -methyluronamides ( 7a and 7b) exhibited nanomolar range of binding affinity ( K i = 0.38 nM and 0.28 nM, respectively) at the human A 3AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway. 相似文献
6.
Many studies suggest that adenosine modulates cell responses in a wide array of tissues through potent and selective regulation of cytokine production. This study examined the effects of adenosine on interleukin (IL)‐6 expression and its related signal pathways in mouse embryonic stem (ES) cells. In this study, the adenosine analogue 5′‐ N‐ethylcarboxamide (NECA) increased IL‐6 protein expression level. Mouse ES cells expressed the A 1, A 2A, A 2B, and A 3 adenosine receptors (ARs), whose expression levels were increased by NECA and NECA‐induced increase of IL‐6 mRNA expression or secretion level was inhibited by the non‐specific AR inhibitor, caffeine. NECA increased Akt and protein kinase C (PKC) phosphorylation, intracellular Ca 2+ and cyclic adenosine monophosphate (cAMP) levels, which were blocked by caffeine. On the other hand, NECA‐induced IL‐6 secretion was partially inhibited by Akt inhibitor, bisindolylmaleimide I (PKC inhibitor), SQ 22536 (adenylate cyclate inhibitor) and completely blocked by the 3 inhibitor combination treatment. In addition, NECA increased mitogen activated protein kinase' (MAPK) phosphorylation, which were partially inhibited by the Akt inhibitor, bisindolylmaleimide I, and SQ 22536 and completely blocked by the 3 inhibitor combination treatment. NECA‐induced increases of IL‐6 protein expression and secretion levels were inhibited by MAPK inhibition. NECA‐induced increase of nuclear factor (NF)‐κB phosphorylation was inhibited by MAPK inhibitors. NECA also increased cAMP response element‐binding protein (CREB) phosphorylation, which was blocked by MAPK or NF‐κB inhibitors. Indeed, NECA‐induced increase of IL‐6 protein expression and secretion was blocked by NF‐κB inhibitors. In conclusion, NECA stimulated IL‐6 expression via MAPK and NF‐κB activation through Akt, Ca 2+/PKC, and cAMP signaling pathways in mouse ES cells. J. Cell. Physiol. 219: 752–759, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
7.
Previously, we have reported that the coronary reactive hyperemic response was reduced in adenosine A2A receptor-null (A2AAR?/?) mice, and it was reversed by the soluble epoxide hydrolase (sEH) inhibitor. However, it is unknown in aortic vascular response, therefore, we hypothesized that A2AAR-gene deletion in mice (A2AAR?/?) affects adenosine-induced vascular response by increase in sEH and adenosine A1 receptor (A1AR) activities. A2AAR?/? mice showed an increase in sEH, AI AR and CYP450-4A protein expression but decrease in CYP450-2C compared to C57Bl/6 mice. NECA (adenosine-analog) and CCPA (adenosine A1 receptor-agonist)-induced dose-dependent vascular response was tested with t-AUCB (sEH-inhibitor) and angiotensin-II (Ang-II) in A2AAR?/? vs. C57Bl/6 mice. In A2AAR?/?, NECA and CCPA-induced increase in dose-dependent vasoconstriction compared to C57Bl/6 mice. However, NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? was reduced by t-AUCB with NECA. Similarly, dose-dependent vascular contraction in A2AAR?/? was reduced by t-AUCB with CCPA. In addition, Ang-II enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? with NECA. Similarly, the dose-dependent vascular contraction in A2AAR?/? was also enhanced by Ang-II with CCPA. Further, t-AUCB reduced Ang-II-enhanced NECA and CCPA-induced dose-dependent vascular contraction in A2AAR?/? mice. Our data suggest that the dose-dependent vascular contraction in A2AAR?/? mice depends on increase in sEH, A1AR and CYP4A protein expression. 相似文献
8.
Abstract A series of new 2-alkynyl, 2-cycloalkynyl, and 2-aralkynyl derivatives of adenosine-5′-ethyluronamide (NECA) were synthesized and evaluated in binding studies and functional assays to assess their potency and selectivity at A 2 vs A 1 receptors. The new derivatives were also tested as inhibitors of rabbit platelet aggregation induced by ADP. While the presence of an aromatic or heteroaromatic ring conjugated to the triple bond decreased antiplatelet activity, the introduction of a hydroxyl group or a heterocyclic ring on the alkynyl side chain increased the antiaggregatory activity in comparison with NECA, resulting in the most potent inhibitors of platelet aggregation so far known in the nucleoside series. However, the presence of an α-quaternary carbon markedly reduced the antiaggregatory potency without affecting the A 2 binding affinity, suggesting that the platelet receptor is not a typical A 2a site. 相似文献
9.
Abstract Synthesis of 3′-deoxy-3′-fluoro- N 6-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A 3 adenosine receptor are described. 相似文献
10.
AbstractThe binding characteristics of radiolabeled N 6-(cyclohexyl)adenosine ([ 3H]CHA), N 6-(R-phenylisopropyl)adenosine ([ 3H]R-PIA), 5′-N-ethylcarboxamidoadenosine ([ 3H]NECA), and 2-[4-(2-carboxyethyl)phenyl]ethyl-amino-5′-N-ethylcarboxamidoadenosine ([ 3H]CGS 21680), to rat testis membranes were investigated. Specific binding of [ 3H]CGS 21680, a selective agonist for the A 2a adenosine receptor, was very modest whilst the nonselective agonist [ 3H]NECA bound to rat testis membranes showing high binding capacity. At least two types of binding sites for [ 3H]NECA could be identified in rat testis membranes: high affinity sites and high capacity sites. Selective agonists for the At adenosine receptor, [ 3H]CHA and [ 3H]R-PIA bound with high affinity to a single class of binding sites. This high affinity binding site showed the typical pharmacological specificity of the A 1 adenosine receptor with a potency order for agonists of CHA R-PIA > NECA > N 6-(S-phenylisopropyl)adenosine (S-PIA). In order to detect the presence of the A 3 adenosine receptor in these membranes we selectively blocked the A 1 receptor with a large molar excess of a xanthine antagonist, either 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or xanthine amine congener (XAC). In the presence of an antagonist a low affinity binding site for [ 3H]CHA and [ 3H]R-PIA was detected. This low affinity binding site showed a different pharmacological specificity than the high affinity binding site. In fact the potency order for agonists was CHA NECA = R-PIA > S-PIA. This finding suggests that the low affinity binding site represents the A 3 adenosine receptor. 相似文献
11.
Several N 6 -substituted 3 ′-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A 3 adenosine receptor (AR) agonists. Among compounds tested, 3 ′-ureido- N 6 -(3-iodobenzyl)adenosine ( 2c ) exhibited the highest binding affinity ( K i = 0.22 μ M) at the H272E mutant A 3 AR without binding to the natural A 3 AR. 相似文献
12.
Abstract Full adenosine A 1 receptor agonists like CPA and other N 6- ?substituted adenosine analogs have previously been shown to become partial agonists upon deletion of the 3′-hydroxyl moiety. The present study further explored the C-3′ site for modification. The modest affinity at A 1 and A 2a receptors found in the 3′-amido-3′-deoxyxyIofuranosyladenine series prompted us to synthesize the corresponding N 6- ?cyclopentyl derivatives, which proved to exhibit potent antagonistic behaviour at the A 1 receptors. This represents a new perspective in the purinergic field. 相似文献
13.
Adenosine 5′-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of Mycobacterium tuberculosis during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5′-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of N6-substituted adenosine analogues and their 5′-phosphates as well as adenosine 5′-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5′-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors. 相似文献
14.
The G protein-coupled A 2A adenosine receptor represents an important drug target. Crystal structures and modeling studies indicated that three disulfide bonds are formed between ECL1 and ECL2 (I, Cys71 2.69-Cys159 45.43; II, Cys74 3.22-Cys146 45.30, and III, Cys77 3.25-Cys166 45.50). However, the A 2BAR subtype appears to require only disulfide bond III for proper function. In this study, each of the three disulfide bonds in the A 2AAR was disrupted by mutation of one of the cysteine residues to serine. The mutant receptors were stably expressed in Chinese hamster ovary cells and analyzed in cyclic adenosine monophosphate (cAMP) accumulation and radioligand binding studies using structurally diverse agonists: adenosine, NECA, CGS21680, and PSB-15826. Results were rationalized by molecular modeling. The observed effects were dependent on the investigated agonist. Loss of disulfide bond I led to a widening of the orthosteric binding pocket resulting in a strong reduction in the potency of adenosine, but not of NECA or 2-substituted nucleosides. Disruption of disulfide bond II led to a significant reduction in the agonists’ efficacy indicating its importance for receptor activation. Disulfide bond III disruption reduced potency and affinity of the small adenosine agonists and NECA, but not of the larger 2-substituted agonists. While all the three disulfide bonds were essential for high potency or efficacy of adenosine, structural modification of the nucleoside could rescue affinity or efficacy at the mutant receptors. At present, it cannot be excluded that formation of the extracellular disulfide bonds in the A 2AAR is dynamic. This might add another level of G protein-coupled receptor (GPCR) modulation, in particular for the cysteine-rich A 2A and A 2BARs. 相似文献
15.
Abstract Several deaza-analogues of adenosine and 2-chloro-adenosine have been examined for their adenosine receptor affinity. It was found that the relative contribution of the nitrogen atoms of the purine moiety to binding at A 1 rat brain adenosine receptor, follows the order N 7 > N 3 > N 1. The affinity of the adenosine analogues for the adenosine rat brain receptor was besides compared with their activity as inhibitors of platelet aggregation. A synthesis of 2-chloro-1-deazaadenosine by two alternative routes starting from 7-nitroimidazo[4,5-b]pyridine-4-oxide is also reported. 相似文献
17.
Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626–629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and retroviruses. Among the most potent SAH hydrolase inhibitors and antiviral agents rank carbocyclic 3-deazaadenosine (C-c 3Ado), neplanocin A, 3-deazaneplanocin A, the 5′-nor derivatives of carbocyclic adenosine (C-Ado, aristeromycin), and the 2-halo (i.e., 2-fluoro) and 6′- R-alkyl (i.e., 6′ -R-methyl) derivatives of neplanocin A. These compounds are particularly active against poxviruses (i.e., vaccinia virus), and rhabdoviruses (i.e., vesicular stomatitis virus). The in vivo efficacy of C-c 3Ado and 3-deazaneplanocin A has been established in mouse models for vaccinia virus, vesicular stomatitis virus, and Ebola virus. SAH hydrolase inhibitors such as C-c 3Ado and 3-deazaneplanocin A should in the first place be considered for therapeutic (or prophylactic) use against poxvirus infections, including smallpox, and hemorrhagic fever virus infections such as Ebola. 相似文献
18.
A selective agonist radioligand for A 2B adenosine receptors (A 2BARs) is currently not available. Such a tool would be useful for labeling the active conformation of the receptors. Therefore, we prepared BAY 60-6583, a potent and functionally selective A 2BAR (partial) agonist, in a tritium-labeled form. Despite extensive efforts, however, we have not been able to establish a radioligand binding assay using [ 3H]BAY 60-6583. This is probably due to its high non-specific binding and its moderate affinity, which had previously been overestimated based on functional data. As an alternative, we evaluated the non-selective A 2BAR agonist [ 3H]NECA for its potential to label A 2BARs. [ 3H]NECA showed specific, saturable, and reversible binding to membrane preparations of Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells stably expressing human, rat, or mouse A 2BARs. In competition binding experiments, the AR agonists 2-chloroadenosine (CADO) and NECA displayed significantly higher affinity when tested versus [ 3H]NECA than versus the A 2B-antagonist radioligand [ 3H]PSB-603 while structurally diverse AR antagonists showed the opposite effects. Although BAY 60-6583 is an A 2BAR agonist, it displayed higher affinity versus [ 3H]PSB-603 than versus [ 3H]NECA. These results indicate that nucleoside and non-nucleoside agonists are binding to very different conformations of the A 2BAR. In conclusion, [ 3H]NECA is currently the only useful radioligand for determining the affinity of ligands for an active A 2BAR conformation. 相似文献
19.
Abstract Room-temperature treatment of persilylated 6-chloro-9-β-D-ribofuranosyl-purine with a variety of aliphatic and aromatic amines, in the presence of Pd 2(dba) 3, BINAP and base, leads to N 6-substituted adenosine analogues in fair to good yields. Coupling of chloropurine with a chiral aziridinyl diester is applied in the synthesis of a potential adenylosuccinate lyase inhibitor. 相似文献
20.
Human reproduction is complex and prone to failure. Though causes of miscarriage remain unclear, adenosine, a proangiogenic nucleoside, may help determine pregnancy outcome. Although adenosine receptor (AR) expression has been characterized in euploid pregnancies, no information is available for aneuploidies, which, as prone to spontaneous abortion (SA), are a potential model for shedding light on the mechanism regulating this event. AR expression was investigated in 71 first-trimester chorionic villi (CV) samples and cultured mesenchymal cells (MC) from euploid and TR21 pregnancies, one of the most frequent autosomal aneuploidy, with a view to elucidating their potential role in the modulation of vascular endothelial growth factor (VEGF) and nitric oxide (NO). Compared to euploid cells, reduced A 1 and A 2B expression was revealed in TR21 CV and MCs. The non-selective adenosine agonist 5′- N-ethylcarboxamidoadenosine (NECA) increased NO, by activating, predominantly, A 1AR and A 2AAR through a molecular pathway involving hypoxia-inducible-factor-1 (HIF-1α), and increased VEGF, mainly through A 2B. In conclusion the adenosine transduction cascade appears to be disturbed in TR21 through reduced expression of A 2B and A 1ARs. These anomalies may be implicated in complications such as fetal growth restriction, malformation and/or SA, well known features of aneuploid pregnancies. Therefore A 1 and A 2BARs could be potential biomarkers able to provide an early indication of SA risk and their stimulation may turn out to improve fetoplacental perfusion by increasing NO and VEGF. 相似文献
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