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1.
Adenosine A 2A receptor (A 2AR) is a G protein-coupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A 2AR expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A 2AR expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A 2AR messenger RNA (mRNA) and protein content as well as A 2AR-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A 2AR expression could be established. Overall, we concluded that striatal A 2AR functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A 2AR expression. 相似文献
2.
6-Hydroxydopamine (6-OHDA) is the most used toxin in experimental Parkinson’s disease (PD) models. 6-OHDA shows high affinity for the dopamine transporter and once inside the neuron, it accumulates and undergoes non-enzymatic auto-oxidation, promoting reactive oxygen species (ROS) formation and selective damage of catecholaminergic neurons. In this way, our group has established a 6-OHDA in vitro protocol with rat striatal slices as a rapid and effective model for screening of new drugs with protective effects against PD. We have shown that co-incubation with guanosine (GUO, 100 μM) prevented the 6-OHDA-induced damage in striatal slices. As the exact GUO mechanism of action remains unknown, the aim of this study was to investigate if adenosine A1 (A1R) and/or A2A receptors (A2AR) are involved on GUO protective effects on striatal slices. Pre-incubation with DPCPX, an A1R antagonist prevented guanosine effects on 6-OHDA-induced ROS formation and mitochondrial membrane potential depolarization, while CCPA, an A1R agonist, did not alter GUO effects. Regarding A2AR, the antagonist SCH58261 had similar protective effect as GUO in ROS formation and mitochondrial membrane potential. Additionally, SCH58261 did not affect GUO protective effects. The A2AR agonist CGS21680, although, completely blocked GUO effects. Finally, the A1R antagonist DPCPX, and the A2AR agonist CGS21680 also abolished the preventive guanosine effect on 6-OHDA-induced ATP levels decrease. These results reinforce previous evidence for a putative interaction of GUO with A1R-A2AR heteromer as its molecular target and clearly indicate a dependence on adenosine receptors modulation to GUO protective effect. 相似文献
3.
It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in
the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A 2A adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression.
Thus, this study was designed to investigate whether cardioprotective A 2A adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected
to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A 2A agonist CGS21680 (0.2 μg/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting
reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size
was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared
to the Control group (34.6 ± 1.8% and 52.3 ± 2.8% respectively; p < 0.05), with no difference com-pared to the Late group (40.1 ± 6.1%). Apoptosis regressi-on was documented in the amygdala
of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to
a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive
cell numbers were not reduced in the Late group. Moreover, TNFα was significantly reduced in the amygdala of the Early group
compared to the Control and Late groups. These results indicate that A 2A adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.
This work was supported by Natural Sciences and Engineering Research Council of Canada (NSERC). 相似文献
4.
Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1Rs) and the less abundant, but widespread, facilitatory A 2ARs. It is commonly assumed that A 1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1Rs in chronic noxious situations. In contrast, A 2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinsons and Alzheimers disease, ischemic brain damage and epilepsy. The greater interest of A 2AR blockade compared to A 1R activation does not mean that A 1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different. 相似文献
5.
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
6.
The aim of the present paper was to examine, in a comparative way, the occurrence and the mechanisms of the interactions between adenosine A 2A receptors (A 2ARs) and metabotropic glutamate 5 receptors (mGlu5Rs) in the hippocampus and the striatum. In rat hippocampal and corticostriatal slices, combined ineffective doses of the mGlu5R agonist 2-chloro-5-hydroxyphenylglycine (CHPG) and the A 2AR agonist CGS 21680 synergistically reduced the slope of excitatory postsynaptic field potentials (fEPSPs) recorded in CA1 and the amplitude of field potentials (FPs) recorded in the dorsomedial striatum. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway appeared to be involved in the effects of CGS 21680 in corticostriatal but not in hippocampal slices. In both areas, a postsynaptic locus of interaction appeared more likely. N-methyl- D-aspartate (NMDA) reduced the fEPSP slope and FP amplitude in hippocampal and corticostriatal slices, respectively. Such an effect was significantly potentiated by CHPG in both areas. Interestingly, the A 2AR antagonist ZM 241385 significantly reduced the NMDA-potentiating effect of CHPG. In primary cultures of rat hippocampal and striatal neurons (ED 17, DIV 14), CHPG significantly potentiated NMDA-induced lactate dehydrogenase (LDH) release. Again, such an effect was prevented by ZM 241385. Our results show that A 2A and mGlu5 receptors functionally interact both in the hippocampus and in the striatum, even though different mechanisms seem to be involved in the two areas. The ability of A 2ARs to control mGlu5R-dependent effects may thus be a general feature of A 2ARs in different brain regions (irrespective of their density) and may represent an additional target for the development of therapeutic strategies against neurological disorders. 相似文献
7.
1. Serotonin is an intrinsically fluorescent biogenic amine that acts as a neurotransmitter and is found in a wide variety of sites in the central and peripheral nervous system. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions.2. Serotonin exerts its diverse actions by binding to distinct cell surface receptors which have been classified into many groups. The serotonin 1A (5-HT 1A) receptor is the most extensively studied of the serotonin receptors and belongs to the large family of seven transmembrane domain G-protein coupled receptors.3. The tissue and sub-cellular distribution, structural characteristics, signaling of the serotonin 1A receptor and its interaction with G-proteins are discussed.4. The pharmacology of serotonin 1A receptors is reviewed in terms of binding of agonists and antagonists and sensitivity of their binding to guanine nucleotides.5. Membrane biology of 5-HT 1A receptors is presented using the bovine hippocampal serotonin 1A receptor as a model system. The ligand binding activity and G-protein coupling of the receptor is modulated by membrane cholesterol thereby indicating the requirement of cholesterol in maintaining the receptor organization and function. This, along with the reported detergent resistance characteristics of the receptor, raises important questions on the role of membrane lipids and domains in the function of this receptor. 相似文献
8.
We investigated the effects of Nigella sativa on apoptosis and gamma-aminobutyric acid (GABA A) receptor density in cerebral cortical and hippocampal neurons in a pentylenetetrazol (PTZ)-induced kindling model in rats. The PTZ kindling model was produced by injecting PTZ in subconvulsive doses to rats on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22 and 24 of the study into animals of PTZ treated (PTZ) and PTZ + N. sativa treated (PTZ + NS) groups. Clonic and tonic seizures were induced by injecting a convulsive dose of PTZ on day 26 of the study. Rats in the PTZ + NS group were treated also with a 10 mg/kg methanolic extract of N. sativa 2 h before each PTZ injection. Rats in the control group were treated with 4 ml/kg saline. The number of neurons that expressed GABA A receptors in the hippocampus and cerebral cortex of rats in the PTZ and PTZ + NS groups increased significantly. There was no significant difference in the number of GABA A receptors between the PTZ and PTZ + NS groups. GABA A receptor density of the neurons in the cerebral cortex, but not hippocampus, was increased in PTZ group compared to controls. We observed a significant increase in the number of apoptotic neurons in the cerebral cortex of rats of both the PTZ and PTZ + NS groups compared to controls. We observed a significant decrease in the number of the apoptotic neurons in the cerebral cortex of rats in the PTZ + NS group compared to the PTZ group. N. sativa treatment ameliorated the PTZ induced neurodegeneration in the cerebral cortex as reflected by neuronal apoptosis and neuronal GABA A receptor frequency. 相似文献
9.
Adenosine A 2a receptor (A 2aR) colocalizes with dopamine D 2 receptor (D 2R) in the basal ganglia and modulates D 2R-mediated dopaminergic activities. A 2aR and D 2R couple to stimulatory and inhibitory G proteins, respectively. Their opposing roles in regulating neuronal activities, such as locomotion and alcohol consumption, are mediated by their opposite actions on adenylate cyclase, which often serves as “co-incidence detector” of various activators. On the other hand, the neural actions of A 2aR and D 2R are also, at least partially, independent of each other, as indicated by studies using D 2R and A 2aR knock-out mice. Here we co-expressed human A 2aR and human D 2LR in CHO cells and examined their signaling characteristics. Human A 2aR desensitized rapidly upon agonist stimulation. A 2aR activity (80%) was diminished after 2 hr of pretreatment with its agonist CGS21680. In contrast, human D 2LR activity was sustained even after 2 hr and 18 hr pretreatment with its agonist quinpirole. Long-term (18 hr) stimulation of human D 2LR also increased basal cAMP levels in CHO cells, whereas long-term (18 hr) activation of human A 2aR did not affect basal cAMP levels. Furthermore, long-term (18 hr) activation of D 2LR dramatically sensitized A 2aR-induced stimulation of adenylate cyclase in a pertussis toxin-sensitive way. Forskolin-induced cAMP accumulation was significantly increased after short-term (2 hr) human D 2LR stimulation and further elevated after long-term (18 hr) D 2LR activation. However, neither short-term (2 hr) nor long-term (18 hr) stimulation of A 2aR affected the inhibitory effects of D 2LR on adenylate cyclase. Co-stimulation of A 2aR and D 2LR could not induce desensitization or sensitization of D 2LR either. In summary, signaling t hrough A 2aR and D 2LR is distinctive and synergistic, supporting their unique and yet integrative roles in regulating neuronal functions when both receptors are present. 相似文献
10.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, enhances synaptic transmission and regulates
neuronal proliferation and survival. Functional interactions between adenosine A 2A receptors (A 2ARs) and BDNF have been recently reported. In this article, we report some recent findings from our group showing that A 2ARs regulate both BDNF functions and levels in the brain. Whereas BDNF (10 ng/ml) increased the slope of excitatory postsynaptic
field potentials (fEPSPs) in hippocampal slices from wild-type (WT) mice, it was completely ineffective in slices taken from
A 2AR knock-out (KO) mice. Furthermore, enzyme immunoassay studies showed a significant reduction in hippocampal BDNF levels in
A 2AR KO vs. WT mice. Having found an even marked reduction in the striatum of A 2AR KO mice, and as both BDNF and A 2ARs have been implicated in the pathogenesis of Huntington’s disease (HD), an inherited striatal neurodegenerative disease,
we then evaluated whether the pharmacological blockade of A 2ARs could influence striatal levels of BDNF in an experimental model of HD-like striatal degeneration (quinolinic acid-lesioned
rats) and in a transgenic mice model of HD (R6/2 mice). In both QA-lesioned rats and early symptomatic R6/2 mice (8 weeks),
the systemic administration of the A 2AR antagonist SCH58261 significantly reduced striatal BDNF levels. These results indicate that the presence and the tonic activation
of A 2ARs are necessary to allow BDNF-induced potentiation of synaptic transmission and to sustain a normal BDNF tone. The possible
functional consequences of reducing striatal BDNF levels in HD models need further investigation. 相似文献
11.
A single serine point mutation (S374A) in the adenosine A 2A receptor (A 2AR) C-terminal tail reduces A 2AR-D 2R heteromerization and prevents its allosteric modulation of the dopamine D 2 receptor (D 2R). By means of site directed mutagenesis of the A 2AR and synthetic transmembrane (TM) α-helix peptides of the D 2R we further explored the role of electrostatic interactions and TM helix interactions of the A 2AR-D 2R heteromer interface. We found evidence that the TM domains IV and V of the D 2R play a major role in the A 2AR-D 2R heteromer interface since the incubation with peptides corresponding to these domains significantly reduced the ability of A 2AR and D 2R to heteromerize. In addition, the incubation with TM-IV or TM-V blocked the allosteric modulation normally found in A 2AR-D 2R heteromers. The mutation of two negatively charged aspartates in the A 2AR C-terminal tail (D401A/D402A) in combination with the S374A mutation drastically reduced the physical A 2AR-D 2R interaction and lost the ability of antagonistic allosteric modulation over the A 2AR-D 2R interface, suggesting further evidence for the existence of an electrostatic interaction between the C-terminal tail of A 2AR and the intracellular loop 3 (IL3) of D 2R. On the other hand, molecular dynamic model and bioinformatic analysis propose that specific AAR, AQE, and VLS protriplets as an important motive in the A 2AR-D 2LR heteromer interface together with D 2LR TM segments IV/V interacting with A 2AR TM-IV/V or TM-I/VII. 相似文献
12.
Adenosine A 2A receptors (A 2ARs) and dopamine D 2 receptors (D 2Rs) form constitutive heteromers in living cells and exhibit a strong functional antagonistic interaction. Recent findings give neurochemical evidence that extended cocaine self-administration in the rat give rise to an up-regulation of functional A 2ARs in the nucleus accumbens that return to baseline expression levels during cocaine withdrawal. In the present work, the acute in vitro effects of a concentration of cocaine known to fully block the dopamine (DA) transporter without exerting any toxic actions were investigated on A 2AR and D 2LR formed heteromers in transiently co-transfected HEK-293T cells. In vitro treatment of cocaine was found to produce changes in D 2R homodimers and in A 2AR-D 2R heterodimers detected through bioluminescent energy transfer (BRET). Cocaine was found to produce a time- and concentration-dependent reduction in the BRET max between A 2AR-D 2LR heterodimers and D 2LR homodimers, but not A 2AR homodimers, indicating its effect on D 2R. Cocaine was evaluated with regard to D 2R binding using a human D 2LR stable expressing CHO cell line and was found to produce an increase in the affinity of hD 2LR for DA. At the level of G protein-coupling, cocaine produced a small, but significant increase in DA-stimulated binding of GTPγS. However, cocaine failed to modulate D 2R agonist-induced inhibition of cAMP in stable hD 2LR CHO cells or the gating of GIRK channels in oocytes. Taken together, these results indicate a direct and specific effect of a moderate concentration of cocaine on the DA D 2LR, that results in enhanced agonist recognition, G protein-coupling and an altered conformational state of D 2R homodimers and A 2AR-D 2R heterodimers. 相似文献
13.
The highly potent but modestly selective N-(2-amino-4-methoxy-benzothiazol-7-yl)- N-ethyl-acetamide derivative 2 was selected as the starting point for the design of novel selective A 2B antagonists, due to its excellent potency, and good drug-like properties. A series of compounds containing nonaromatic amides or ureas of five- or six-membered rings, and also bearing an m-trifluoromethyl-phenyl group (shown to impart superior potency) was prepared and evaluated for their selectivity against the A 2A and A 1 receptors. This work resulted in the identification of compound 30, with excellent potency and high selectivity against both A 2A and A 1 receptors. 相似文献
14.
Chronic granulomatous disease (CGD) is caused by defects in the NADPH oxidase complex and is characterized by an increased susceptibility to infection. Other significant complications of CGD include autoimmunity and non-infectious hyperinflammatory disorders. We show that a gp91 phox deficiency leads to the development of phenotypically altered T lymphocytes in mice and that this abnormal, hyperactive phenotype can be modulated by activation of the adenosine A 2A receptor. T cells isolated from CGD mice produce significantly higher levels of the pro-inflammatory cytokines IFN-γ, IL-2, TNF-α, IL-4 and IL-13 than do WT cells after TCR-mediated activation; treatment with the selective adenosine A 2A receptor agonist, CGS21680, potently inhibits this response. Additionally, the over exuberant inflammatory response elicited by thioglycollate challenge in gp91 phox deficient mice is attenuated by CGS21680. These data suggest that treatment with A 2AR agonists may be an effective therapy by which to regulate the immune system hyperactivity that results from a gp91 phox deficiency. 相似文献
15.
We studied expression of the 5-HT 1A receptor in cortical and limbic areas of the brain of the tree shrew. In situ hybridization with a receptor-specific probe and immunocytochemistry with various antibodies was used to identify distinct neurons expressing the receptor. In vitro receptor autoradiography with 3H-8-OH-DPAT ( 3H-8-hydroxy-2-[di-n-propylamino]tetralin) was performed to visualize receptor-binding sites. In the prefrontal, insular, and occipital cortex, 5-HT 1A receptor mRNA was expressed in pyramidal neurons of layer 2, whereas 3H-8-OH-DPAT labeled layers 1 and 2 generating a columnar-like pattern in the prefrontal and occipital cortex. In the striate and ventral occipital cortex, receptor mRNA was present within layers 5 and 6 in pyramidal neurons and Meynert cells. Pyramid-like neurons in the claustrum and anterior olfactory nucleus also expressed the receptor. Principal neurons in hippocampal region CA1 expressed 5-HT 1A receptor mRNA, and 3H-8-OH-DPAT labeled both the stratum oriens and stratum radiatum. CA3 pyramidal neurons displayed low 5-HT 1A receptor expression, whereas granule neurons in the dentate gyrus revealed moderate expression of this receptor. In the amygdala, large pyramid-like neurons in the basal magnocellular nucleus strongly expressed the receptor. Immunocytochemistry with antibodies against parvalbumin, calbindin, and gamma aminobutyric acid (GABA) provided no evidence for 5-HT 1A receptor expression in GABAergic neurons in cortical and limbic brain areas. Our data agree with previous findings showing that the 5-HT 1A receptor mediates the modulation of glutamatergic neurons. Expression in the limbic and cortical areas suggested an involvement of 5-HT 1A receptors in emotional and cognitive processes.This work was supported by the German Science Foundation (SFB 406; C4 to G.F.). 相似文献
16.
The synthesis of an important set of 3-furfurylxanthine derivatives is described. Binding affinities were determined for rat A 1 and human A 2A, A 2B and A 3 receptors. Several of the 3-furfuryl-7-methylxanthine derivatives showed moderate-to-high affinity at human A 2B receptors, the most active compound ( 10d) having a Ki of 7.4 nM for hA 2B receptors, with selectivities over rA 1 and hA 2A receptors up to 14-fold and 11-fold, respectively. Affinities for hA 3 receptors were very low for all members of the set. 相似文献
17.
The present study was to investigate the role of central 5-HT and 5-HT 1A receptor binding and gene expression in a rat model of pancreatic regeneration using 60% pancreatectomy. The pancreatic regeneration was evaluated by 5-HT content and 5-HT 1A receptor gene expression in the cerebral cortex (CC) and brain stem (BS) of sham operated, 72 h and 7 days pancreatectomised rats. 5-HT content significantly increased in the CC ( P < 0.01) and BS ( P < 0.05) of 72 h pancreatectomised rats. Sympathetic activity was decreased as indicated by the significantly decreased norepinephrine (NE) and epinephrine (EPI) level ( P < 0.001 and P < 0.05) in the plasma of 72 h pancreatectomised rats. 5-HT 1A receptor density and affinity was decreased in the CC ( P < 0.01) and BS ( P < 0.01). These changes correlated with a diminished 5-HT 1Areceptor mRNA expression in the brain regions studied. Our results suggest that the brain 5-HT through 5-HT 1A receptor has a functional role in the pancreatic regeneration through the sympathetic regulation. 相似文献
18.
Neonatal brain hypoxic ischemia (HI) often results in long-term motor and cognitive impairments. Post-ischemic inflammation greatly effects outcome and adenosine receptor signaling modulates both HI and immune cell function. Here, we investigated the influence of adenosine A 1 receptor deficiency (A 1R ?/?) on key immune cell populations in a neonatal brain HI model. Ten-day-old mice were subjected to HI. Functional outcome was assessed by open locomotion and beam walking test and infarction size evaluated. Flow cytometry was performed on brain-infiltrating cells, and semi-automated analysis of flow cytometric data was applied. A 1R ?/? mice displayed larger infarctions (+33 %, p?<?0.05) and performed worse in beam walking tests (44 % more mistakes, p?<?0.05) than wild-type (WT) mice. Myeloid cell activation after injury was enhanced in A 1R ?/? versus WT brains. Activated B lymphocytes expressing IL-10 infiltrated the brain after HI in WT, but were less activated and did not increase in relative frequency in A 1R ?/?. Also, A 1R ?/? B lymphocytes expressed less IL-10 than their WT counterparts, the A 1R antagonist DPCPX decreased IL-10 expression whereas the A 1R agonist CPA increased it. CD4 + T lymphocytes including FoxP3 + T regulatory cells, were unaffected by genotype, whereas CD8 + T lymphocyte responses were smaller in A 1R ?/? mice. Using PCA to characterize the immune profile, we could discriminate the A 1R ?/? and WT genotypes as well as sham operated from HI-subjected animals. We conclude that A 1R signaling modulates IL-10 expression by immune cells, influences the activation of these cells in vivo, and affects outcome after HI. 相似文献
19.
The structural and functional interaction between D 2 dopamine receptor (DR) and A 2A adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D 2DR induces a significant negative regulation of A 2AAR-mediated responses, whereas few data are at now available about the regulation of A 2AAR by D 2DR agonists at receptor recognition site. In this work we confirmed that in A 2AAR/D 2DR co-transfected cells, these receptors exist as homo- and hetero-dimers. The classical D 2DR agonists were able to negatively modulate both A 2AAR affinity and functionality. These effects occurred even if any significant changes in A 2AAR/D 2DR energy transfer interaction could be detected in BRET experiments.Since the development of new molecules able to target A 2A/D 2 dimers may represent an attractive tool for innovative pharmacological therapy, we also identified a new small molecule, 3-(3,4-dimethylphenyl)-1-(2-piperidin-1-yl)ethyl)piperidine (compound 1), full agonist of D 2DR and modulator of A 2A-D 2 receptor dimer. This compound was able to negatively modulate A 2AAR binding properties and functional responsiveness in a manner comparable to classical D 2R agonists. In contrast to classical agonists, compound 1 led to conformational changes in the quaternary structure in D 2DR homomers and heteromers and induced A 2AAR/D 2DR co-internalization. These results suggest that compound 1 exerts a high control of the function of heteromers and could represent a starting point for the development of new drugs targeting A 2AAR/D 2 DR heteromers. 相似文献
20.
The molecular interaction between adenosine A 2A and dopamine D 2 receptors (A 2ARs and D 2Rs, respectively) within an oligomeric complex has been postulated to play a pivotal role in the adenosine–dopamine interplay in the central nervous system, in both normal and pathological conditions (e.g. Parkinson’s disease). While the effects of A 2AR challenge on D 2R functioning have been largely studied, the reverse condition is still unexplored, a fact that might have impact in therapeutics. Here, we aimed to examine in a real-time mode the D 2R-mediated allosteric modulation of A 2AR binding when an A 2AR/D 2R oligomer is established. Thus, we synthesized fluorescent A 2AR agonists and evaluated, by means of a flow cytometry homogeneous no-wash assay and a real-time fluorescence resonance energy transfer (FRET)-based approach, the effects on A 2AR binding of distinct antiparkinsonian drugs in current clinical use (i.e. pramipexole, rotigotine and apomorphine). Our results provided evidence for the existence of a differential D 2R-mediated negative allosteric modulation on A 2AR agonist binding that was oligomer-formation dependent, and with apomorphine being the best antiparkinsonian drug attenuating A 2AR agonist binding. Overall, the here-developed methods were found valid to explore the ability of drugs acting on D 2Rs to modulate A 2AR binding, thus serving to facilitate the preliminary selection of D 2R-like candidate drugs in the management of Parkinson’s disease. 相似文献
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