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1.
Animal models of asthma have shown that limonene, a naturally occurring terpene in citrus fruits, can reduce inflammation and airway reactivity. However, the mechanism of these effects is unknown. We first performed computational and molecular docking analyses that showed limonene could bind to both A2A and A2B receptors. The pharmacological studies were carried out with A2A adenosine receptor knock-out (A2AKO) and wild-type (WT) mice using ovalbumin (OVA) to generate the asthma phenotype. We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) and NECA (nonselective adenosine analog) by administering limonene as an inhalation prior to OVA aerosol challenges in one group of allergic mice for both WT and KO. In whole-body plethysmography studies, we observed that airway responsiveness to MCh in WT SEN group was significantly lowered upon limonene treatment but no effect was observed in A2AKO. Limonene also attenuated NECA-induced airway responsiveness in WT allergic mice with no effect being observed in A2AKO groups. Differential BAL analysis showed that limonene reduced levels of eosinophils in allergic WT mice but not in A2AKO. However, limonene reduced neutrophils in sensitized A2AKO mice, suggesting that it may activate A2B receptors as well. These data indicate that limonene-induced reduction in airway inflammation and airway reactivity occurs mainly via activation of A2AAR but A2B receptors may also play a supporting role. 相似文献
2.
Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin‐induced airway inflammation and airway hyper‐responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti‐asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A‐activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A 3 (A 3 AR), which mediates mast cell‐dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2‐driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A 3 AR and PDE4 activities. 相似文献
3.
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
4.
The discovery of new drugs for the treatment of neurodegenerative disorders, such as Parkinson's disease, has become an attractive field of research. Due to the regulation of D 2 receptor activity by A 2 A adenosine receptor, potent and selective ligands of A 2 A subtype could be useful tools to study neurodegenerative disorders. A series of 2,8-disubstituted-9-ethyladenine derivatives was synthesized and tested in binding affinity assay at human adenosine receptors. New compounds showed good affinity and selectivity at A 2 A receptor versus the other subtypes. The introduction of a bromine atom in 8-position increased the affinity of these compounds, leading to ligands with K i in the nanomolar range. 相似文献
6.
The development of adenosine A 2A receptor antagonists has received much interest in recent years for the treatment of neurodegenerative diseases. Based on docking studies, a new series of 2-arylbenzoxazoles has been identified as potential A 2AR antagonists. Structure-affinity relationship was investigated in position 2, 5 and 6 of the benzoxazole heterocycle leading to compounds with a micromolar affinity towards the A 2A receptor. Compound F1, with an affinity of 1?μm, presented good absorption, distribution, metabolism and excretion properties with an excellent aqueous solubility (184?μm) without being cytotoxic at 100?μm. This compound, along with low-molecular weight compound D1 ( Ki?=?10?μm), can be easily modulated and thus considered as relevant starting points for further hit-to-lead optimisation. 相似文献
7.
The synthesis of a series of 9-ethyladenine derivatives bearing alkynyl chains in 2- or 8-position was undertaken, based on the observation that replacement of the sugar moiety in adenosine derivatives with alkyl groups led to adenosine receptor antagonists. All the synthesized compounds were tested for their affinity at human and rat A 1, A 2A, and A 3 adenosine receptors in binding assays; the activity at the human A 2B receptor was determined in adenylyl cyclase experiments. Biological data showed that the 2-alkynyl derivatives possess good affinity and are slightly selective for the human A 2A receptor. The same compounds tested on the rat A 1 and A 2A subtypes showed in general lower affinity for both receptors. On the other hand, the affinity of the 8-alkynyl derivatives at the human A 1, A 2A, and A 2B receptors proved to be lower than that of the corresponding 2-alkynyl derivatives. On the contrary, the affinity of the same compounds for the human A 3 receptor was improved, resulting in A 3 selectivity. As in the case of the 2-alkynyl-substituted compounds, the 8-alkynyl derivatives showed decreased affinity for rat receptors. However, it is worthwhile to note that the 8-phenylethynyl-9-ethyladenine was the most active compound of the two series ( Ki in the nanomolar range) at both the human and rat A 3 subtype. Docking experiments of the 2- and 8-phenylethynyl-9-ethyladenines, at a rhodopsin-based homology model, gave a rational explanation of the preference of the human A 3 receptor for the 8-substituted compound. 相似文献
8.
The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N1 ( 1, 2) or N10 ( 3, 4) nitrogen of a triazinobenzimidazole scaffold, were synthesized. The compounds were biologically evaluated as fluorescent probes for labelling A 1 and A 2B AR subtypes in bone marrow-derived mesenchymal stem cells (BM-MSCs) that express both receptor subtypes. The binding affinity of the synthetized compounds towards the different AR subtypes was determined. The probe 3 revealed a higher affinity to A 1 and A 2B ARs, showing interesting spectroscopic properties, and it was selected as the most suitable candidate to label both AR subtypes in undifferentiated MSCs.Fluorescence confocal microscopy showed that compound 3 significantly labelled ARs on cell membranes and the fluorescence signal was decreased by the cell pre-incubation with the A 1 AR and A 2B AR selective agonists, R-PIA and BAY 60-6583, respectively, thus confirming the specificity of the obtained signal. In conclusion, compound 3 could represent a useful tool to investigate the expression pattern of both A 1 and A 2B ARs in different pathological and physiological processes. Furthermore, these results provide an important basis for the design of new and more selective derivatives able to monitor the expression and localization of each different ARs in several tissues and living cells. 相似文献
9.
A new series of 1 H‐imidazol‐1‐yl substituted 8‐phenylxanthine analogs has been synthesized to study the effects of the imidazole group on the binding affinity of compounds for adenosine receptors. Competition binding studies of these compounds were carried out in vitro with human cloned receptors using [ 3H]DPCPX and [ 3H]ZM 241385 as radioligands at A 1 and A 2A adenosine receptors, respectively. The effect of the substitution pattern of the (imidazolyl)alkoxy group on various positions of the phenyl ring at C(8) was also studied. The xanthine derivatives displayed varying degrees of affinity and selectivity towards A 1 and A 2A receptor subtypes despite a common but variedly substituted Ar C(8). 相似文献
10.
Inosine, a naturally occurring purine formed from the breakdown of adenosine, is associated with immunoregulatory effects. Evidence shows that inosine modulates lung inflammation and regulates cytokine generation. However, its role in controlling allergen-induced lung inflammation has yet to be identified. In this study, we aimed to investigate the role of inosine and adenosine receptors in a murine model of lung allergy induced by ovalbumin (OVA). Intraperitoneal administration of inosine (0.001–10 mg/kg, 30 min before OVA challenge) significantly reduced the number of leukocytes, macrophages, lymphocytes and eosinophils recovered in the bronchoalveolar lavage fluid of sensitized mice compared with controls. Interestingly, our results showed that pre-treatment with the selective A 2A receptor antagonist (ZM241385), but not with the selective A 2B receptor antagonist (alloxazine), reduced the inhibitory effects of inosine against macrophage count, suggesting that A 2A receptors mediate monocyte recruitment into the lungs. In addition, the pre-treatment of mice with selective A 3 antagonist (MRS3777) also prevented inosine effects against macrophages, lymphocytes and eosinophils. Histological analysis confirmed the effects of inosine and A 2A adenosine receptors on cell recruitment and demonstrated that the treatment with ZM241385 and alloxazine reverted inosine effects against mast cell migration into the lungs. Accordingly, the treatment with inosine reduced lung elastance, an effect related to A 2 receptors. Moreover, inosine reduced the levels of Th 2-cytokines, interleukin-4 and interleukin-5, an effect that was not reversed by A 2A or A 2B selective antagonists. Our data show that inosine acting on A 2A or A 3 adenosine receptors can regulate OVA-induced allergic lung inflammation and also implicate inosine as an endogenous modulator of inflammatory processes observed in the lungs of asthmatic patients. 相似文献
11.
This paper describes the synthesis of novel 7-amino-thiazolo[5,4- d]pyrimidines bearing different substituents at positions 2, 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2– 27 were evaluated in radioligand binding (A 1, A 2A and A 3) and adenylyl cyclase activity (A 2B and A 2A) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes. The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo[5,4- d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A 2A, A 1 and A 3 structures. 相似文献
12.
Bronchospasm induced by adenosine is blocked by representatives of all the major classes of drugs used in the treatment of asthma. Understanding the mechanism of this bronchospasm may help understand the way these drugs work. Clinical studies have suggested involvement of neural pathways, mast-like cells and mediators such as histamine, serotonin and lipoxygenase products. There is a strong link between responsiveness to adenosine and eosinophilia. In different animal models A1, A2b and A3 adenosine receptor subclasses have all been implicated in inducing bronchospasm. whilst occupation of the A2a receptor generally has no, or the opposite effect. At least two different mechanisms, both involving neural pathways, exist. One, involving the adenosine A1 receptor, functions in mast cell depleted animals; the other requires interaction with a population of mast-like cells activated over A2b or A3 receptors. Not only histamine but also serotonin and lipoxygenase products released from the mast-like cells are potential mediators. In animal models good reactivity to adenosine receptor agonists is generally only found when the animals are first sensitized and exposed to allergen in ways likely to induce an allergic inflammation. An exception is the BDE rat, which reacts to adenosine receptor agonists such as APNEA or NECA even without allergen exposure. This rat strain does however show evidence of spontaneous eosinophilic inflammation in the lung even without immunization. As mast cells both release adenosine and respond to adenosine, adenosine provides a non-specific method of amplifying specific signals resulting from IgE/antigen interaction. This mechanism may not only have a pathological significance in asthma; it may be part of a normal bodily defense response that in asthmatic subjects is inappropriately activated. 相似文献
13.
Etodolac, which inhibits the activity of cyclooxygenase, did not affect antigen-induced contractions of the trachea and lung parenchyma of guinea pigs. Indomethacin tended to enhance antigen-induced contractions of the trachea and significantly enhanced contractions of the lung parenchyma. The inhibitory activity of AA-861, a 5-lipoxygenase inhibitor, in antigen-induced contractions of the trachea and lung parenchyma was more potent than that of ozagrel, a thromboxane A 2 (TXA 2) inhibitor. Thus, lipoxygenase products played a more important role than TXA 2 in antigen-induced contractions of the trachea and lung parenchyma. These results suggest that the enhancement of antigen-induced contractions by indomethacin might be due to an increase in anaphylactic release of lipoxygenase products through the inhibition of cyclooxygenase. Since etodolac did not enhance antigen-induced contractions, we attempted to determine whether or not etodolac inhibits 5-lipoxygenase. Etodolac was found to have no effect on 5-lipoxygenase activity. Therefore, the low adverse effect of etodolac on antigen-induced contractions of the airway may be due to its weak inhibition of cyclooxygenase in the airway. These results suggest that etodolac would have only a very slight, if any, adverse effect on the airway in patients with asthma. 相似文献
14.
Abstract In a search for potent and selective adenosine agonists it has been found that 2-hexynyladenosine-5′-N-ethyluronamide (HENECA) displays high affinity at rat A 2A receptor combined with a good A 2A vs A 1 selectivity. The finding that HENECA shows good affinity also for A 3 receptors prompted us to investigate the effect of various substituents in different positions of this molecule. 相似文献
16.
Prior studies demonstrate that adenosine, acting at one or more of its receptors, mediates the anti-inflammatory effects of
methotrexate in animal models of both acute and chronic inflammation. Both adenosine A 2A and A 3 receptors contribute to the anti-inflammatory effects of methotrexate treatment in the air pouch model of inflammation, and
the regulation of inflammation by these two receptors differs at the cellular level. Because different factors may regulate
inflammation at different sites we examined the effect of low-dose weekly methotrexate treatment (0.75 mg/kg/week) in a model
of acute peritoneal inflammation in adenosine A 2A receptor knockout mice and A 3 receptor knockout mice and their wild-type littermates. Following intraperitoneal injection of thioglycollate there was no
significant difference in the number or type of leukocytes, tumor necrosis factor alpha (TNF-α) and IL-10 levels that accumulated
in the thioglycollate-induced peritoneal exudates in adenosine A 2A knockout mice or wild-type control mice. In contrast, there were more leukocytes, TNF-α and IL-10 in the exudates of the
adenosine A 3 receptor-deficient mice. Low-dose, weekly methotrexate treatment increased the adenosine concentration in the peritoneal
exudates of all mice studied, and reduced the leukocyte accumulation in the wild-type mice and A 3 receptor knockout mice but not in the A 2A receptor knockout mice. Methotrexate reduced exudate levels of TNF-α in the wild-type mice and A 3 receptor knockout mice but not the A 2A receptor knockout mice. More strikingly, IL-10, a critical regulator of peritoneal inflammation, was increased in the methotrexate-treated
wild-type mice and A 3 knockout mice but decreased in the A 2A knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was similarly effective in
wild-type mice, A 2A mice and A 3 knockout mice. These findings provide further evidence that adenosine is a potent regulator of inflammation that mediates
the anti-inflammatory effects of methotrexate. Moreover, these data provide strong evidence that the anti-inflammatory effects
of methotrexate and adenosine are mediated by different receptors in different inflammatory loci, an observation that may
explain why inflammatory diseases of some organs but not of other organs respond to methotrexate therapy. 相似文献
17.
Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti‐inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A 1 receptor, phosphatidylinositol‐3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin‐sensitive G‐protein‐coupled signaling, blockade of adenosine A 2A receptors (A 2AR), but not via A 1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake. 相似文献
18.
Abstract: To clarify the effects of adenosine receptor subtypes (A 1, A 2, and A 3) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5-HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A 1 receptor agonist, 2-chloro- N6-cyclopentyladenosine, decreased extracellular 5-HT levels, whereas an adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), and caffeine increased these levels. A selective A 2A receptor agonist (CGS-21680), an adenosine A 2 receptor agonist (PD-125944), an adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), and an adenosine A 3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5-HT levels. When the adenosine A 1 receptor was blocked by CPT, the hippocampal extracellular 5-HT level was increased by adenosine, CGS-21680, and PD-125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A 1 and A 2 receptors were blocked by CPT and DMPX, the extracellular 5-HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5-HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A 1 receptor was blocked, irrespective of whether the adenosine A 2 receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5-HT levels, during both adenosine A 1 and A 2 receptor blockade, were inhibited by selective 5-HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A 2 receptor and the inhibitory effects of the A 3 receptor on hippocampal extracellular 5-HT levels are masked by the inhibitory effects of the adenosine A 1 receptor. 相似文献
19.
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
20.
BackgroundClinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13. MethodsThe effect of poly IC on allergen-induced airway eosinophilia was investigated for mast cell-conserved Kit +/+ mice and -deficient Kit W/Kit W-v mice. The outcome of mast cell reconstitution was further investigated. ResultsAirway eosinophilia and IL-13 production were augmented by poly IC in Kit +/+ mice but not in Kit W/Kit W-v mice. When Kit W/Kit W-v mice were reconstituted with bone marrow-derived mast cells (BMMCs), the augmentation was restored. The augmentation was not induced in the mice systemically deficient for TIR domain-containing adaptor-inducing IFN-β (TRIF) or interferon regulatory factor (IRF)-3, both mediate dsRNA-triggered innate immune responses. The augmentation was, however, restored in Kit W/Kit W-v mice reconstituted with TRIF-deficient or IRF-3-deficient BMMCs. Although leukotriene B 4 and prostaglandin D 2 are major lipid mediators released from activated mast cells, no their contribution was shown to the dsRNA-induced augmentation of airway eosinophilia. ConclusionsWe conclude that mast cells contribute to dsRNA-induced augmentation of allergic airway inflammation without requiring direct activation of mast cells with dsRNA or involvement of leukotriene B 4 or prostaglandin D 2. 相似文献
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