417 results on '"Adenosine A3 Receptor Antagonists"'
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2. Activation of adenosine A3 receptor reduces early brain injury by alleviating neuroinflammation after subarachnoid hemorrhage in elderly rats
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Zhengyuan Xia, Bin Yi, Xinchuan Wei, Dan-Dan Wang, Chunxia Luo, Karine Belguise, Yujie Li, Peng Deng, Xiaobo Wang, Xue-Hong Bai, Peng Li, and Xiaojun Li
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Agonist ,Aging ,medicine.drug_class ,subarachnoid hemorrhage ,Pyridines ,microglial polarization ,Adenosine A3 Receptor Antagonists ,Brain damage ,Pharmacology ,Neuroprotection ,p38 Mitogen-Activated Protein Kinases ,Proinflammatory cytokine ,Adenosine A3 Receptor Agonists ,medicine ,adenosine A3 receptor ,Animals ,cardiovascular diseases ,Neuroinflammation ,Inflammation ,Microglia ,business.industry ,Receptor, Adenosine A3 ,Imidazoles ,Brain ,Cell Biology ,Adenosine A3 receptor ,Adenosine receptor ,anti-inflammation ,nervous system diseases ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Pyrimidines ,Brain Injuries ,Gene Knockdown Techniques ,Cytokines ,medicine.symptom ,business ,STAT6 Transcription Factor ,Research Paper ,Signal Transduction - Abstract
The incidence of subarachnoid hemorrhage (SAH) and hazard ratio of death increase with age. Overactivation of microglia contributes to brain damage. This study aimed to investigate the effects of A3 adenosine receptors (A3R) activation on neurofunction and microglial phenotype polarization in the context of SAH in aged rats. The A3R agonist (CI-IB-MECA) and antagonist (MRS1523) were used in the SAH model. Microglia were cultured to mimic SAH in the presence or absence of CI-IB-MECA and/or siRNA for A3R. The neurofunction and status of the microglial phenotype were evaluated. The P38 inhibitor SB202190 and the STAT6 inhibitor AS1517499 were used to explore the signaling pathway. The results showed that SAH induced microglia to polarize to the M(LPS) phenotype both in vivo and in vitro. CI-IB-MECA distinctly skewed microglia towards the M(IL-4) phenotype and ameliorated neurological dysfunction, along with the downregulation of inflammatory cytokines. Knockdown of A3R or inhibition of P38 and/or STAT6 weakened the effects of CI-IB-MECA on microglial phenotypic shifting. Collectively, our findings suggest that activation of A3R exerted anti-inflammatory and neuroprotective effects by regulating microglial phenotype polarization through P38/STAT6 pathway and indicated that A3R agonists may be a promising therapeutic options for the treatment of brain injury after SAH.
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- 2020
3. Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis
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György Haskó, William C. Gause, Jennet Beesley, Pal Pacher, Zoltan H. Nemeth, and Marianna Lovászi
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Inosine monophosphate ,Adenosine monophosphate ,Male ,Receptor, Adenosine A2A ,Purine nucleoside phosphorylase ,Adenosine A3 Receptor Antagonists ,Pharmacology ,Receptor, Adenosine A2B ,Biochemistry ,Article ,chemistry.chemical_compound ,Mice ,Inosine Monophosphate ,Guanosine monophosphate ,Genetics ,medicine ,Animals ,Purine metabolism ,Inosine ,Molecular Biology ,Hypoxanthine ,Tumor Necrosis Factor-alpha ,Receptor, Adenosine A3 ,Pneumonia, Pneumococcal ,Triazoles ,Endotoxemia ,Adenosine A2 Receptor Antagonists ,Interleukin-10 ,Mice, Inbred C57BL ,Disease Models, Animal ,Streptococcus pneumoniae ,chemistry ,Quinazolines ,Nucleoside ,Biotechnology ,medicine.drug ,Signal Transduction - Abstract
Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown. In this study, we demonstrate that IMP suppressed tumor necrosis factor (TNF)-α production and augmented IL-10 production in endotoxemic mice. IMP exerted its effects through metabolism to inosine, as IMP only suppressed TNF-α following its CD73-mediated degradation to inosine in lipopolysaccharide-activated macrophages. Studies with gene targeted mice and pharmacological antagonism indicated that A2A , A2B, and A3 adenosine receptors are not required for the inosine suppression of TNF-α production. The inosine suppression of TNF-α production did not require its metabolism to hypoxanthine through purine nucleoside phosphorylase or its uptake into cells through concentrative nucleoside transporters indicating a role for alternative metabolic/uptake pathways. Inosine augmented IL-β production by macrophages in which inflammasome was activated by lipopolysaccharide and ATP. In contrast to its effects in endotoxemia, IMP failed to affect the inflammatory response to abdominal sepsis and pneumonia. We conclude that extracellular IMP and inosine differentially regulate the inflammatory response.
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- 2021
4. Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A
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Yoonji, Lee, Xiyan, Hou, Jin Hee, Lee, Akshata, Nayak, Varughese, Alexander, Pankaz K, Sharma, Hyerim, Chang, Khai, Phan, Zhan-Guo, Gao, Kenneth A, Jacobson, Sun, Choi, and Lak Shin, Jeong
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Models, Molecular ,Protein Conformation ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Molecular Dynamics Simulation ,Ligands ,Article ,Structure-Activity Relationship ,Cricetulus ,HEK293 Cells ,Models, Chemical ,Adenosine A3 Receptor Agonists ,Catalytic Domain ,Cricetinae ,Animals ,Humans - Abstract
Distinguishing compounds’ agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (K(i) = 2.40 nM) as a potent human A(3) adenosine receptor (hA(3)AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA(3)AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor–ligand complex, the results indicated that the hydrogen bonding with Thr94(3.36) and His272(7.43) could make a stable interaction between the 3′-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds’ actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.
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- 2021
5. Pharmacological characterization of DPTN and other selective A
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Zhan-Guo, Gao, R Rama, Suresh, and Kenneth A, Jacobson
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Mice ,HEK293 Cells ,Receptor, Adenosine A3 ,Cyclic AMP ,Adenosine A3 Receptor Antagonists ,Animals ,Humans ,Original Article ,Rats - Abstract
The A(3) adenosine receptor (AR) is emerging as an attractive drug target. Antagonists are proposed for the potential treatment of glaucoma and asthma. However, currently available A(3)AR antagonists are potent in human and some large animals, but weak or inactive in mouse and rat. In this study, we re-synthesized a previously reported A(3)AR antagonist, DPTN, and evaluated its affinity and selectivity at human, mouse, and rat ARs. We showed that DPTN, indeed, is a potent A(3)AR antagonist for all three species tested, albeit a little less selective for mouse and rat A(3)AR in comparison to the human A(3)AR. DPTN’s K(i) values at respective A(1), A(2A), A(2B), and A(3) receptors were (nM) 162, 121, 230, and 1.65 (human); 411, 830, 189, and 9.61 (mouse); and 333, 1147, 163, and 8.53 (rat). Its antagonist activity at both human and mouse A(3)ARs was confirmed in a cyclic AMP functional assay. Considering controversial use of currently commercially available A(3)AR antagonists in rats and mice, we also re-examined other commonly used and selective A(3)AR antagonists under the same experimental conditions. The K(i) values of MRS1523 were shown to be 43.9, 349, and 216 nM at human, mouse, and rat A(3)ARs, respectively. MRS1191 and MRS1334 showed incomplete inhibition of [(125)I]I-AB-MECA binding to mouse and rat A(3)ARs, while potent human A(3)AR antagonists, MRS1220, MRE3008F20, PSB10, PSB-11, and VUF5574 were largely inactive. Thus, we demonstrated that DPTN and MRS1523 are among the only validated A(3)AR antagonists that can be possibly used (at an appropriate concentration) in mouse or rat to confirm an A(3)AR-related mechanism or function. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11302-021-09823-5.
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- 2021
6. Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice
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Jaemin Lee, Tomoe Yashiro, Syed Faisal Zaidi, Makoto Kadowaki, Takeshi Yamamoto, Hanako Ogata, and Shusaku Hayashi
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Nervous system ,Male ,QH301-705.5 ,FcεRI ,Intracellular Space ,Adenosine A3 Receptor Antagonists ,Myenteric Plexus ,Bone Marrow Cells ,Cell Communication ,Biology ,Immunoglobulin E ,Models, Biological ,Article ,Enteric Nervous System ,Immune system ,Calcium imaging ,medicine ,Animals ,Mast Cells ,RNA, Messenger ,Biology (General) ,Antigens ,Intestinal Mucosa ,Receptor ,Cells, Cultured ,enteric neuron ,Neurons ,Mice, Inbred BALB C ,food allergy ,mucosal mast cell ,Receptors, IgE ,Receptor, Adenosine A3 ,General Medicine ,Adenosine A3 receptor ,Adenosine ,Mice, Inbred C57BL ,medicine.anatomical_structure ,adenosine ,neuro-immune interaction ,Immunology ,biology.protein ,Cholinergic ,Food Hypersensitivity ,medicine.drug - Abstract
Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.
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- 2021
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7. Development of Covalent, Clickable Probes for Adenosine A
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Phuc N H, Trinh, Daniel J W, Chong, Katie, Leach, Stephen J, Hill, Joel D A, Tyndall, Lauren T, May, Andrea J, Vernall, and Karen J, Gregory
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Azides ,Receptor, Adenosine A1 ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Adenosine A1 Receptor Antagonists ,Ligands ,Cricetulus ,Alkynes ,Drug Design ,Molecular Probes ,Xanthines ,Animals ,Humans ,Click Chemistry ,Fluorescent Dyes - Abstract
Adenosine receptors are attractive therapeutic targets for multiple conditions, including ischemia-reperfusion injury and neuropathic pain. Adenosine receptor drug discovery efforts would be facilitated by the development of appropriate tools to assist in target validation and direct receptor visualization in different native environments. We report the development of the first bifunctional (chemoreactive and clickable) ligands for the adenosine A
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- 2021
8. Sexually dimorphic therapeutic response in bortezomib-induced neuropathic pain reveals altered pain physiology in female rodents
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Kenneth A. Jacobson, Gina L. C. Yosten, Zhoumou Chen, Carrie Wahlman, Willis K. Samson, Timothy M. Doyle, Katherine Stockstill, Dilip K. Tosh, Daniela Salvemini, and Kathryn Braden
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Male ,Sphingosine 1 Phosphate Receptor Modulators ,Spinal Cord Dorsal Horn ,Paclitaxel ,medicine.medical_treatment ,Receptor expression ,Adenosine A3 Receptor Antagonists ,Antineoplastic Agents ,Pharmacology ,Duloxetine Hydrochloride ,Article ,Bortezomib ,03 medical and health sciences ,chemistry.chemical_compound ,Sex Factors ,0302 clinical medicine ,030202 anesthesiology ,medicine ,Animals ,Duloxetine ,Sphingosine-1-Phosphate Receptors ,S1PR1 ,Chemotherapy ,Morphine ,Fingolimod Hydrochloride ,business.industry ,Multiple sclerosis ,Receptor, Adenosine A3 ,medicine.disease ,Rats ,Analgesics, Opioid ,Oxaliplatin ,Anesthesiology and Pain Medicine ,Neurology ,chemistry ,Neuropathic pain ,Neuralgia ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Chemotherapy-induced neuropathic pain (CINP) in both sexes compromises many current chemotherapeutics and lacks an FDA-approved therapy. We recently identified the sphingosine-1-phosphate receptor subtype 1 (S1PR1) and A3 adenosine receptor subtype (A3AR) as novel targets for therapeutic intervention. Our work in male rodents using paclitaxel, oxaliplatin, and bortezomib showed robust inhibition of CINP with either S1PR1 antagonists or A3AR agonists. The S1PR1 functional antagonist FTY720 (Gilenya) is FDA-approved for treating multiple sclerosis, and selective A3AR agonists are in advanced clinical trials for cancer and inflammatory disorders, underscoring the need for their expedited trials in patients with CINP as chemotherapy adjuncts. Our findings reveal that S1PR1 antagonists and A3AR agonists mitigate paclitaxel and oxaliplatin CINP in female and male rodents, but failed to block or reverse bortezomib-induced neuropathic pain (BINP) in females. Although numerous mechanisms likely underlie these differences, we focused on receptor levels. We found that BINP in male rats, but not in female rats, was associated with increased expression of A3AR in the spinal cord dorsal horn, whereas S1PR1 levels were similar in both sexes. Thus, alternative mechanisms beyond receptor expression may account for sex differences in response to S1PR1 antagonists. Morphine and duloxetine, both clinical analgesics, reversed BINP in female mice, demonstrating that the lack of response is specific to S1PR1 and A3AR agents. Our findings suggest that A3AR- and S1PR1-based therapies are not viable approaches in preventing and treating BINP in females and should inform future clinical trials of these drugs as adjuncts to chemotherapy.
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- 2019
9. Indirect Medium Spiny Neurons in the Dorsomedial Striatum Regulate Ethanol-Containing Conditioned Reward Seeking
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Doo Sup Choi, Sa Ik Hong, Jiang-Fan Chen, and Seungwoo Kang
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Male ,0301 basic medicine ,Agonist ,medicine.drug_class ,Adenosine A3 Receptor Antagonists ,Adenosine A2A receptor ,Stimulation ,Optogenetics ,Globus Pallidus ,Medium spiny neuron ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Reward ,Adenosine A3 Receptor Agonists ,medicine ,Animals ,Premovement neuronal activity ,Research Articles ,Neurons ,Ethanol ,Receptors, Adenosine A2 ,Chemistry ,General Neuroscience ,Adenosine ,Mice, Inbred C57BL ,Alcoholism ,030104 developmental biology ,Globus pallidus ,Conditioning, Operant ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Adenosine 2A receptor (A(2A)R)-containing indirect medium spiny neurons (iMSNs) in the dorsomedial striatum (DMS) contribute to reward-seeking behaviors. However, those roles for ethanol-seeking behaviors remain unknown. To investigate ethanol-seeking behaviors, we used an ethanol-containing reward (10% ethanol and 10% sucrose solution; 10E10S). Upon conditioning with 10E10S, mice that initially only preferred 10% sucrose, not 10E10S, showed a stronger preference for 10E10S. Then, we investigated whether the manipulation of the DMS–external globus pallidus (GPe) iMSNs circuit alters the ethanol-containing reward (10E10S) seeking behaviors using the combination of pharmacologic and optogenetic approaches. DMS A(2A)R activation dampened operant conditioning-induced ethanol-containing reward, whereas A(2A)R antagonist abolished the effects of the A(2A)R agonist and restored ethanol-containing reward-seeking. Moreover, pre-ethanol exposure potentiated the A(2A)R-dependent reward-seeking. Interestingly, mice exhibiting ethanol-containing reward-seeking showed the reduction of the DMS iMSNs activity, suggesting that disinhibiting iMSNs decreases reward-seeking behaviors. In addition, we found that A(2A)R activation reversed iMSNs neural activity in the DMS. Similarly, optogenetic stimulation of the DMS-GPe iMSNs reduced ethanol-containing reward-seeking, whereas optogenetic inhibition of the DMS-GPe iMSNs reversed this change. Together, our study demonstrates that DMS A(2A)R and iMSNs regulate ethanol-containing reward-seeking behaviors. SIGNIFICANCE STATEMENT Our findings highlight the mechanisms of how operant conditioning develops the preference of ethanol-containing conditioned reward. Mice exhibiting ethanol-containing reward-seeking showed a reduction of the indirect medium spiny neuronal activity in the dorsomedial striatum. Pharmacological activation of adenosine A(2A) receptor (A(2A)R) or optogenetic activation of indirect medium spiny neurons dampened operant conditioned ethanol-containing reward-seeking, whereas inhibiting this neuronal activity restored ethanol-containing reward-seeking. Furthermore, repeated intermittent ethanol exposure potentiated A(2A)R-dependent reward-seeking. Therefore, our finding suggests that A(2A)R-containing indirect medium spiny neuronal activation reduces ethanol-containing reward-seeking, which may provide a potential therapeutic target for alcohol use disorder.
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- 2019
10. A live cell NanoBRET binding assay allows the study of ligand-binding kinetics to the adenosine A3 receptor
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Stephen J. Hill, Lizi Xia, Monica Bouzo-Lorenzo, Adriaan P. IJzerman, Laura H. Heitman, Leigh A. Stoddart, and Stephen J. Briddon
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0301 basic medicine ,Kinetics ,Adenosine A3 Receptor Antagonists ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Fluorescence Resonance Energy Transfer ,Humans ,Adenosine A3 receptor ,Receptor ,Molecular Biology ,Chemistry ,Residence time ,NanoBRET ,Ligand binding assay ,Receptor, Adenosine A3 ,Antagonist ,Cell Biology ,Fluorescence ,Receptor–ligand kinetics ,3. Good health ,HEK293 Cells ,030104 developmental biology ,Binding kinetics ,Luminescent Measurements ,Biophysics ,Original Article ,Adenosine A(3) receptor ,Lead compound ,030217 neurology & neurosurgery - Abstract
There is a growing interest in understanding the binding kinetics of compounds that bind to G protein-coupled receptors prior to progressing a lead compound into clinical trials. The widely expressed adenosine A3 receptor (A3AR) has been implicated in a range of diseases including immune conditions, and compounds that aim to selectively target this receptor are currently under development for arthritis. Kinetic studies at the A3AR have been performed using a radiolabelled antagonist, but due to the kinetics of this probe, they have been carried out at 10 °C in membrane preparations. In this study, we have developed a live cell NanoBRET ligand binding assay using fluorescent A3AR antagonists to measure kinetic parameters of labelled and unlabelled compounds at the A3AR at physiological temperatures. The kinetic profiles of four fluorescent antagonists were determined in kinetic association assays, and it was found that XAC-ser-tyr-X-BY630 had the longest residence time (RT = 288 ± 62 min) at the A3AR. The association and dissociation rate constants of three antagonists PSB-11, compound 5, and LUF7565 were also determined using two fluorescent ligands (XAC-ser-tyr-X-BY630 or AV039, RT = 6.8 ± 0.8 min) as the labelled probe and compared to those obtained using a radiolabelled antagonist ([3H]PSB-11, RT = 44.6 ± 3.9 min). There was close agreement in the kinetic parameters measured with AV039 and [3H]PSB-11 but significant differences to those obtained using XAC-S-ser-S-tyr-X-BY630. These data indicate that selecting a probe with the appropriate kinetics is important to accurately determine the kinetics of unlabelled ligands with markedly different kinetic profiles.
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- 2019
11. Amitriptyline inhibits the MAPK/ERK and CREB pathways and proinflammatory cytokines through A3AR activation in rat neuropathic pain models
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Jin A Kim, Yoo Jung Park, Jin Woo Choi, Hong Soo Jung, Jang Hyeok In, So Young Kwon, Yong Shin Kim, Yumi Kim, and Jin Deok Joo
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Male ,MAP Kinase Signaling System ,Amitriptyline ,medicine.medical_treatment ,Adenosine A3 Receptor Antagonists ,Pharmacology ,CREB ,Proinflammatory cytokine ,lcsh:RD78.3-87.3 ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,030202 anesthesiology ,medicine ,Animals ,Experimental Research Article ,Extracellular Signal-Regulated MAP Kinases ,Cytokine ,biology ,business.industry ,Receptor, Adenosine A3 ,Antagonist ,030208 emergency & critical care medicine ,Mitogen-activated protein kinase ,Cyclic AMP response element-binding protein ,Adenosine ,Rats ,Disease Models, Animal ,Anesthesiology and Pain Medicine ,Nociception ,lcsh:Anesthesiology ,Adenosine A3 ,Neuropathic pain ,biology.protein ,Cytokines ,Neuralgia ,business ,medicine.drug - Abstract
Background The pain-relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype overexpressed in inflammatory and cancer cells. This study was performed to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. Methods Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague-Dawley rats. The neuropathic rats were randomly assigned to one of the following three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and 3-ethyl-5-benzyl- 2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS) group. Amitriptyline or saline was administered intraperitoneally and 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191), an A3AR antagonist, was injected subcutaneously immediately before amitriptyline administration. The level of extracellular signal-regulated kinase P44/42 (ERK1/2), cyclic AMP response element-binding protein (CREB), and proinflammatory cytokines were assessed using immunoblotting or reverse-transciption polymerase chain reaction. Results Amitriptyline increased the mechanical withdrawal threshold of the neuropathic rats. The level of phospho-ERK1/2 and phospho-CREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline administration not only reduced the threshold of mechanical allodynia, but also increased the signaling protein and proinflammatory cytokine levels, which were reduced by amitriptyline. Conclusions The results of this study suggest that the anti-nociceptive effect of amitriptyline involves the suppression of ERK1/2 and CREB signaling proteins, and A3AR activation also affects the alleviation of the inflammatory response.
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- 2019
12. Pharmacological characterisation of novel adenosine A3 receptor antagonists
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Barkan, Kerry, Lagarias, Panagiotis, Stampelou, Margarita, Stamatis, Dimitrios, Hoare, Sam, Safitri, Dewi, Klotz, Karl-Norbert, Vrontaki, Eleni, Kolocouris, Antonios, Ladds, Graham, Ladds, Graham [0000-0001-7320-9612], and Apollo - University of Cambridge Repository
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Binding Sites ,Receptor, Adenosine A3 ,Drug Evaluation, Preclinical ,Receptors, Purinergic P1 ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Molecular Dynamics Simulation ,Binding, Competitive ,Recombinant Proteins ,Rats ,Kinetics ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Species Specificity ,Cyclic AMP ,Mutagenesis, Site-Directed ,Animals ,Humans - Abstract
The adenosine A3 receptor (A3R) belongs to a family of four adenosine receptor (AR) subtypes which all play distinct roles throughout the body. A3R antagonists have been described as potential treatments for numerous diseases including asthma. Given the similarity between (adenosine receptors) orthosteric binding sites, obtaining highly selective antagonists is a challenging but critical task. Here we screen 39 potential A3R, antagonists using agonist-induced inhibition of cAMP. Positive hits were assessed for AR subtype selectivity through cAMP accumulation assays. The antagonist affinity was determined using Schild analysis (pA2 values) and fluorescent ligand binding. Structure-activity relationship investigations revealed that loss of the 3-(dichlorophenyl)-isoxazolyl moiety or the aromatic nitrogen heterocycle with nitrogen at α-position to the carbon of carboximidamide group significantly attenuated K18 antagonistic potency. Mutagenic studies supported by molecular dynamic simulations combined with Molecular Mechanics-Poisson Boltzmann Surface Area calculations identified the residues important for binding in the A3R orthosteric site. We demonstrate that K18, which contains a 3-(dichlorophenyl)-isoxazole group connected through carbonyloxycarboximidamide fragment with a 1,3-thiazole ring, is a specific A3R (< 1 µM) competitive antagonist. Finally, we introduce a model that enables estimates of the equilibrium binding affinity for rapidly disassociating compounds from real-time fluorescent ligand-binding studies. These results demonstrate the pharmacological characterisation of a selective competitive A3R antagonist and the description of its orthosteric binding mode. Our findings may provide new insights for drug discovery.
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- 2020
13. Pharmacological characterisation of novel adenosine A
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Kerry, Barkan, Panagiotis, Lagarias, Margarita, Stampelou, Dimitrios, Stamatis, Sam, Hoare, Dewi, Safitri, Karl-Norbert, Klotz, Eleni, Vrontaki, Antonios, Kolocouris, and Graham, Ladds
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Binding Sites ,Receptor, Adenosine A3 ,Drug Evaluation, Preclinical ,Receptors, Purinergic P1 ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Molecular Dynamics Simulation ,Binding, Competitive ,Recombinant Proteins ,Article ,Rats ,Kinetics ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Species Specificity ,Receptor pharmacology ,Cyclic AMP ,Mutagenesis, Site-Directed ,Animals ,Humans ,Extracellular signalling molecules ,Molecular modelling - Abstract
The adenosine A3 receptor (A3R) belongs to a family of four adenosine receptor (AR) subtypes which all play distinct roles throughout the body. A3R antagonists have been described as potential treatments for numerous diseases including asthma. Given the similarity between (adenosine receptors) orthosteric binding sites, obtaining highly selective antagonists is a challenging but critical task. Here we screen 39 potential A3R, antagonists using agonist-induced inhibition of cAMP. Positive hits were assessed for AR subtype selectivity through cAMP accumulation assays. The antagonist affinity was determined using Schild analysis (pA2 values) and fluorescent ligand binding. Structure–activity relationship investigations revealed that loss of the 3-(dichlorophenyl)-isoxazolyl moiety or the aromatic nitrogen heterocycle with nitrogen at α-position to the carbon of carboximidamide group significantly attenuated K18 antagonistic potency. Mutagenic studies supported by molecular dynamic simulations combined with Molecular Mechanics—Poisson Boltzmann Surface Area calculations identified the residues important for binding in the A3R orthosteric site. We demonstrate that K18, which contains a 3-(dichlorophenyl)-isoxazole group connected through carbonyloxycarboximidamide fragment with a 1,3-thiazole ring, is a specific A3R (
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- 2020
14. Structure-Based Optimization of Coumarin hA
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Maria João, Matos, Santiago, Vilar, Saleta, Vazquez-Rodriguez, Sonja, Kachler, Karl-Norbert, Klotz, Michela, Buccioni, Giovanna, Delogu, Lourdes, Santana, Eugenio, Uriarte, and Fernanda, Borges
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Models, Molecular ,Structure-Activity Relationship ,Coumarins ,Drug Design ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,Humans ,Crystallography, X-Ray - Abstract
Adenosine receptors participate in many physiological functions. Molecules that may selectively interact with one of the receptors are favorable multifunctional chemical entities to treat or decelerate the evolution of different diseases. 3-Arylcoumarins have already been studied as neuroprotective agents by our group. Here, differently 8-substituted 3-arylcoumarins are complementarily studied as ligands of adenosine receptors, performing radioligand binding assays. Among the synthesized compounds, selective A
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- 2019
15. Insights to the Binding of a Selective Adenosine A
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Panagiotis, Lagarias, Kerry, Barkan, Eva, Tzortzini, Margarita, Stampelou, Eleni, Vrontaki, Graham, Ladds, and Antonios, Kolocouris
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Molecular Docking Simulation ,Mutagenesis ,Protein Conformation ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,Thermodynamics ,Poisson Distribution ,gamma-Globulins ,Molecular Dynamics Simulation ,Amides ,Melphalan ,Protein Binding ,Substrate Specificity - Abstract
Adenosine A
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- 2019
16. Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A3receptor antagonists: SAR and molecular modeling studies
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Sonja Kachler, Jitendra C. Kaila, Amit N. Pandya, Dhaivat H. Pandya, Kamala K. Vasu, Veronica Salmaso, Hitesh B. Jalani, Stefano Moro, Karl-Norbert Klotz, and Arshi B. Baraiya
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0301 basic medicine ,Pharmacology ,Adenosine A3 Receptor Antagonists ,Molecular model ,Biochemistry ,Molecular Medicine ,3003 ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,Antagonist ,Pharmaceutical Science ,Xanthine ,Adenosine A3 receptor ,Adenosine receptor ,Adenosine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Drug Discovery ,medicine ,Receptor ,medicine.drug - Abstract
A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A1, A2A and A3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A1, A2A and A3 receptor subtypes.
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- 2018
17. Free-Energy Calculations for Bioisosteric Modifications of A
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Zuzana, Jandova, Willem, Jespers, Eddy, Sotelo, Hugo, Gutiérrez-de-Terán, and Chris, Oostenbrink
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Molecular Docking Simulation ,Binding Sites ,Receptor, Adenosine A3 ,Adenosine receptor ,Adenosine A3 Receptor Antagonists ,free energy calculations ,molecular dynamics simulations ,Molecular Dynamics Simulation ,Groningen Molecular Simulation packace (GROMOS) ,Article ,Protein Binding - Abstract
Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A3 adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol.
- Published
- 2019
18. Blockade of the Adenosine A
- Author
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Wallys, Garrido, Claudia, Jara, Angelo, Torres, Raibel, Suarez, Claudio, Cappelli, Carlos, Oyarzún, Claudia, Quezada, and Rody, San Martín
- Subjects
Male ,Adenosine Deaminase ,diabetic nephropathy ,Caspase 1 ,Interleukin-1beta ,Interleukin-18 ,Adenosine A3 Receptor Antagonists ,interleukins 1 and 18 ,renal fibrosis ,Streptozocin ,Article ,Cell Line ,Diabetes Mellitus, Experimental ,Rats ,Disease Models, Animal ,Kidney Tubules ,Gene Expression Regulation ,inflammasome ,Animals ,Humans ,Diabetic Nephropathies ,adenosine receptor ,Injections, Intraperitoneal - Abstract
Diabetic nephropathy (DN) is the main cause of end-stage renal disease, which remains incurable. The progression of DN is associated with progressive and irreversible renal fibrosis and also high levels of adenosine. Our aim was to evaluate the effects of ADORA3 antagonism on renal injury in streptozotocin-induced diabetic rats. An ADORA3 antagonist that was administered in diabetic rats greatly inhibited the levels of inflammatory interleukins IL-1β and IL-18, meanwhile when adenosine deaminase was administered, there was a non-selective attenuation of the inflammatory mediators IL-1β, IL-18, IL-6, and induction of IL-10. The ADORA3 antagonist attenuated the high glucose-induced activation of caspase 1 in HK2 cells in vitro. Additionally, ADORA3 antagonisms blocked the increase in caspase 1 and the nuclear localization of NFκB in the renal tubular epithelium of diabetic rats, both events that are involved in regulating the production and activation of IL-1β and IL-18. The effects of the A3 receptor antagonist resulted in the attenuation of kidney injury, as evidenced by decreased levels of the pro-fibrotic marker α-SMA at histological levels and the restoration of proteinuria in diabetic rats. We conclude that ADORA3 antagonism represents a potential therapeutic target that mechanistically works through the selective blockade of the NLRP3 inflammasome.
- Published
- 2019
19. Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents
- Author
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Raghu Prasad Mailavaram, Shinjita Ghosh, Omar Al-Attraqchi, and Supratik Kar
- Subjects
Drug ,media_common.quotation_subject ,Adenosine A3 Receptor Antagonists ,Bioinformatics ,Ligands ,01 natural sciences ,Neuroprotection ,03 medical and health sciences ,Immune system ,Adenosine A3 Receptor Agonists ,Drug Discovery ,Medicine ,Humans ,Receptor ,030304 developmental biology ,G protein-coupled receptor ,media_common ,Pharmacology ,0303 health sciences ,business.industry ,Receptor, Adenosine A3 ,Cancer ,Adenosine A3 receptor ,medicine.disease ,Adenosine receptor ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug Design ,business - Abstract
Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.
- Published
- 2019
20. Perspective and Potential of A2A and A3 Adenosine Receptors as Therapeutic Targets for the Treatment of Rheumatoid Arthritis
- Author
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Shantanu Bandopadhyay, Nabamita Bandyopadhyay, Rashmi Saxena Pal, Yogendra Pal, and Sarfaraz Ahmed
- Subjects
Adenosine ,Receptor, Adenosine A2A ,Adenosine A3 Receptor Antagonists ,Inflammation ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Humans ,Receptor ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,030203 arthritis & rheumatology ,Pharmacology ,0303 health sciences ,business.industry ,Receptor, Adenosine A3 ,medicine.disease ,Adenosine receptor ,Adenosine A2 Receptor Antagonists ,Methotrexate ,Rheumatoid arthritis ,Antirheumatic Agents ,Cancer research ,medicine.symptom ,Signal transduction ,business ,medicine.drug ,Signal Transduction - Abstract
Adenosine is a purine nucleoside which is an effective controller of inflammation. The inflammatory effect of adenosine is expressed via its four receptor subtypes viz. A1, A2A, A2B and A3. The various inflammatory conditions including rheumatoid arthritis (RA) are initiated by adenosine receptors of which A2A and A3 play a vital role. RA primarily is an auto-immune disorder which is manifested as chronic inflammation in the synovial lining of joints. In order to develop an effective treatment, the role of cytokines, IL–1, TNF-α and IL–6 is crucial. Besides, the knowledge of PI3K-PKB/Akt and NF-kB signaling pathway is also important to understand the antiinflammatory targets. Methotrexate along with various other molecules like, NSAIDs and DMARDs are presently used as treatment lines for controlling RA. The enhanced knowledge of the preclinical stages and pathogenesis along with recent potent therapeutics raises the hopes that RA can be prevented in the near future.
- Published
- 2019
21. Involvement of A
- Author
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Grazia, Maugeri, Agata Grazia, D'Amico, Concetta, Federico, Salvatore, Saccone, Salvatore, Giunta, Sebastiano, Cavallaro, and Velia, D'Agata
- Subjects
Vascular Endothelial Growth Factor A ,Neuroblastoma ,Adenosine ,Adenosine A3 Receptor Agonists ,Brain Neoplasms ,MAP Kinase Signaling System ,Cell Line, Tumor ,Receptor, Adenosine A3 ,Basic Helix-Loop-Helix Transcription Factors ,Adenosine A3 Receptor Antagonists ,Humans ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell Hypoxia - Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood. The clinical course may range from spontaneous regression towards ganglioneuroblastoma/ganglioneuroma or maturation to a very aggressive form characterized by an extensive hypoxic area. In solid tumors, extracellular microenvironment hypoxia induces the transcription of hypoxia-inducible factors (HIFs) leading to synthesis of pro-angiogenic factor, VEGF; also, it increases extracellular adenosine production from ATP breakdown. To date, the role of this nucleoside in the hypoxic/angiogenic pathway characterizing the core of cancer mass has not been investigated yet. Therefore, the aim of the present study was to analyze the adenosine effect on modulation of the HIF-1α/2α/VEGF pathway mediated through A
- Published
- 2019
22. Development of Covalent Ligands for G Protein-Coupled Receptors: A Case for the Human Adenosine A
- Author
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Xue, Yang, Jacobus P D, van Veldhoven, Jelle, Offringa, Boaz J, Kuiper, Eelke B, Lenselink, Laura H, Heitman, Daan, van der Es, and Adriaan P, IJzerman
- Subjects
Structure-Activity Relationship ,Binding Sites ,Cricetulus ,Guanosine 5'-O-(3-Thiotriphosphate) ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,Animals ,Humans ,CHO Cells ,Ligands - Abstract
[Image: see text] The development of covalent ligands for G protein-coupled receptors (GPCRs) is not a trivial process. Here, we report a streamlined workflow thereto from synthesis to validation, exemplified by the discovery of a covalent antagonist for the human adenosine A(3) receptor (hA(3)AR). Based on the 1H,3H-pyrido[2,1-f]purine-2,4-dione scaffold, a series of ligands bearing a fluorosulfonyl warhead and a varying linker was synthesized. This series was subjected to an affinity screen, revealing compound 17b as the most potent antagonist. In addition, a nonreactive methylsulfonyl derivative 19 was developed as a reversible control compound. A series of assays, comprising time-dependent affinity determination, washout experiments, and [(35)S]GTPγS binding assays, then validated 17b as the covalent antagonist. A combined in silico hA(3)AR-homology model and site-directed mutagenesis study was performed to demonstrate that amino acid residue Y265(7.36) was the unique anchor point of the covalent interaction. This workflow might be applied to other GPCRs to guide the discovery of covalent ligands.
- Published
- 2019
23. Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy
- Author
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Jin Joo Cha, Jung Yeon Ghee, Young Sun Kang, Jee Young Han, Hye Sook Min, Hyunwook Kim, Lak Shin Jeong, Ji Eun Lee, Jung Eun Kim, Kitae Kim, and Dae Ryong Cha
- Subjects
0301 basic medicine ,Male ,Adenosine ,Adenosine A3 Receptor Antagonists ,Dinoprost ,Kidney ,Podocyte ,Mice ,Mice, Inbred BALB C ,Lipid peroxide ,biology ,NF-kappa B ,General Medicine ,Immunohistochemistry ,Proteinuria ,medicine.anatomical_structure ,Adenosine Receptor Antagonist ,Nephrology ,Creatinine ,Original Article ,Kidney Diseases ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,Adenosine receptor antagonist ,Nephropathy ,Nephrin ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Adriamycin ,Internal medicine ,Plasminogen Activator Inhibitor 1 ,medicine ,Albuminuria ,Animals ,Mouse Model ,business.industry ,Body Weight ,Glomerulosclerosis ,Membrane Proteins ,medicine.disease ,Actins ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Doxorubicin ,biology.protein ,Lipid Peroxidation ,business - Abstract
The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF-β1, MCP-1, PAI-1, type IV collagen, NF-κB, NOX4, TLR4, TNFα, IL-1β, and IFN-γ, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX-induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria., Graphical Abstract
- Published
- 2016
24. Novel Oral Therapies for Psoriasis and Psoriatic Arthritis
- Author
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Zenas Z N Yiu and Richard B. Warren
- Subjects
Niacinamide ,Oncology ,Pathology ,medicine.medical_specialty ,Adenosine ,Adenosine A3 Receptor Antagonists ,Administration, Oral ,Arthritis ,Adamantane ,Dermatology ,Biological Factors ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Psoriatic arthritis ,0302 clinical medicine ,Pharmacotherapy ,Piperidines ,Psoriasis ,Internal medicine ,medicine ,Humans ,Pyrroles ,Protein Kinase Inhibitors ,Janus Kinases ,Clinical Trials as Topic ,Sulfonamides ,rho-Associated Kinases ,Tofacitinib ,business.industry ,Arthritis, Psoriatic ,General Medicine ,medicine.disease ,Thalidomide ,Biological Therapy ,Clinical trial ,Receptors, Lysosphingolipid ,Thiazoles ,Pyrimidines ,Ponesimod ,Purines ,030220 oncology & carcinogenesis ,Azetidines ,Pyrazoles ,Phosphodiesterase 4 Inhibitors ,Apremilast ,Isonicotinic Acids ,business ,medicine.drug - Abstract
Several classes of new oral therapy are in use or in development for the treatment of psoriasis. Despite the high efficacy of biologics, new oral therapies remain important as patients generally prefer this mode of administration and they offer an alternative risk-benefit profile. In this review, we discuss the novel modes of action of these drugs, including modulation of cellular pathways involving diverse targets such as Janus kinase, phosphodiesterase 4, sphingosine 1-phosphate, A3 adenosine receptor and rho-associated kinase 2. We review the available evidence around licensed drugs (apremilast) and drugs that are advanced (tofacitinib) or early (ponesimod, baricitinib, peficitinib, INCB039110, CF101, KD025) in the development pipeline. The key limitations of these oral therapies are their modest efficacy profile (apremilast, ponesimod) and the limitations of their safety profile (tofacitinib, ponesimod), while the evidence for the early pipeline drugs are at phase II level only. Potential niches of current unmet needs include apremilast for patients with concomitant psoriatic arthritis, as combination treatments with biologic therapies, and/or for patients in whom multiple biologic therapies have failed due to immunogenicity and secondary inefficacy. The present knowledge gap regarding these novel drugs includes the need for longer clinical trials or observational studies to evaluate safety, and randomised phase III trials for the early pipeline drugs. We conclude that further research and data are necessary to conclusively establish the role of these agents in the current psoriasis treatment paradigm.
- Published
- 2016
25. Adenosine A3 Receptor: A promising therapeutic target in cardiovascular disease
- Author
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Zafar Masood Ansari, Shamama Nishat, Seemi Farhat Basir, and Luqman A. Khan
- Subjects
0301 basic medicine ,Heart Diseases ,Adenosine A3 Receptor Antagonists ,Disease ,Bioinformatics ,Article ,cardiovascular disorder ,03 medical and health sciences ,Adenosine A3 Receptor Agonists ,Cardiovascular Disorder ,Animals ,Humans ,Medicine ,Adenosine A3 receptor ,agonist ,business.industry ,Mechanism (biology) ,Receptor, Adenosine A3 ,antagonist ,General Medicine ,Adenosine receptor ,030104 developmental biology ,Hypertension ,Immunology ,Signal transduction ,signaling ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
Cardiovascular complications are one of the major factors for early mortality in the present worldwide scenario and have become a major challenge in both developing and developed nations. It has thus become of immense importance to look for different therapeutic possibilities and treatments for the growing burden of cardiovascular diseases. Recent advancements in research have opened various means for better understanding of the complication and treatment of the disease. Adenosine receptors have become tool of choice in understanding the signaling mechanism which might lead to the cardiovascular complications. Adenosine A3 receptor is one of the important receptor which is extensively studied as a therapeutic target in cardiovascular disorder. Recent studies have shown that A3AR is involved in the amelioration of cardiovascular complications by altering the expression of A3AR. This review focuses towards the therapeutic potential of A3AR involved in cardiovascular disease and it might help in better understanding of mechanism by which this receptor may prove useful in improving the complications arising due to various cardiovascular diseases. Understanding of A3AR signaling may also help to develop newer agonists and antagonists which might be prove helpful in the treatment of cardiovascular disorder.
- Published
- 2016
26. Adenosine A 3 receptor activation is neuroprotective against retinal neurodegeneration
- Author
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Filipe Elvas, Joana Galvao, Ana Raquel Santiago, Tiago Martins, M Francesca Cordeiro, and António F. Ambrósio
- Subjects
Male ,Adenosine ,N-Methylaspartate ,Cell Survival ,Excitotoxicity ,Adenosine A3 Receptor Antagonists ,Apoptosis ,Kainate receptor ,AMPA receptor ,Biology ,Pharmacology ,medicine.disease_cause ,Retinal ganglion ,Neuroprotection ,Retina ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Organ Culture Techniques ,Adenosine A3 Receptor Agonists ,Excitatory Amino Acid Agonists ,In Situ Nick-End Labeling ,medicine ,Animals ,Rats, Wistar ,Fluorescent Antibody Technique, Indirect ,Receptor, Adenosine A3 ,Retinal Degeneration ,Retinal ,Sensory Systems ,Rats ,Disease Models, Animal ,Ophthalmology ,medicine.anatomical_structure ,Animals, Newborn ,chemistry ,Retinal ganglion cell ,Optic Nerve Injuries ,Intravitreal Injections ,Neuroscience ,Retinal Neurons - Abstract
Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A 3 receptor (A 3 R) in neuroprotection is controversial, A 3 R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A 3 R activation against retinal neurodegeneration. The A 3 R selective agonist (2-Cl-IB-MECA, 1 μM) prevented apoptosis (TUNEL + -cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL + -cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL + -cells/mm 2 in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL + cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V + -cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo . Activation of A 3 R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.
- Published
- 2015
27. Correlation study between A
- Author
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Jinha, Yu, Gyudong, Kim, Dnyandev B, Jarhad, Hyuk Woo, Lee, Jiyoun, Lee, Chong Woo, Park, Hunjoo, Ha, and Lak Shin, Jeong
- Subjects
Structure-Activity Relationship ,Adenosine ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,Animals ,Humans ,Kidney Diseases ,Fibrosis ,Rats - Abstract
Truncated 4'-thionucleosides 1-4 and 4'-oxonucleosides 5-8 as potent and selective A
- Published
- 2018
28. LJ-1888, a selective antagonist for the A3 adenosine receptor, ameliorates the development of atherosclerosis and hypercholesterolemia in apolipoprotein E knock-out mice
- Author
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Se-Jin Jeong, Lak Shin Jeong, Goo Taeg Oh, Gyudong Kim, Jong-Gil Park, and Jinha Yu
- Subjects
0301 basic medicine ,Apolipoprotein E ,Adenosine ,Hypercholesterolemia ,Ischemia ,Adenosine A3 Receptor Antagonists ,030204 cardiovascular system & hematology ,Pharmacology ,Biochemistry ,High-density lipoprotein cholesterol (HDL-chol) ,Bile Acids and Salts ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Low-density lipoprotein cholesterol (LDL-chol) ,Medicine ,Animals ,Risk factor ,Receptor ,Molecular Biology ,Mice, Knockout ,business.industry ,Receptor, Adenosine A3 ,Cancer ,General Medicine ,Articles ,medicine.disease ,Atherosclerosis ,Adenosine receptor ,Plaque, Atherosclerotic ,LJ-1888 ,Biosynthetic Pathways ,030104 developmental biology ,Gene Expression Regulation ,Liver ,Diet, Western ,Rheumatoid arthritis ,Knockout mouse ,lipids (amino acids, peptides, and proteins) ,business ,Transcription Factors - Abstract
Cardiovascular diseases arising from atherosclerosis are the leading causes of mortality and morbidity worldwide. Lipid-lowering agents have been developed in order to treat hypercholesterolemia, a major risk factor for atherosclerosis. However, the prevalence of cardiovascular diseases is increasing, indicating a need to identify novel therapeutic targets and develop new treatment agents. Adenosine receptors (ARs) are emerging as therapeutic targets in asthma, rheumatoid arthritis, cancer, ischemia, and inflammatory diseases. This study assessed whether LJ-1888, a selective antagonist for A3 AR, can inhibit the development of atherosclerosis in apolipoprotein E knock-out (ApoE-/-) mice who are fed a western diet. Plaque formation was significantly lower in ApoE-/- mice administered LJ-1888 than in mice not administered LJ-1888, without any associated liver damage. LJ-1888 treatment of ApoE-/- mice prevented western diet-induced hypercholesterolemia by markedly reducing low-density lipoprotein cholesterol levels and significantly increasing high-density lipoprotein cholesterol concentrations. Reduced hypercholesterolemia in ApoE-/- mice administered LJ-1888 was associated with the enhanced expression of genes involved in bile acid biosynthesis. These findings indicate that LJ-1888, a selective antagonist for A3 AR, may be a novel candidate for the treatment of atherosclerosis and hypercholesterolemia. [BMB Reports 2018; 51(10): 521-526].
- Published
- 2018
29. The Adenosine A3 Receptor Regulates Differentiation of Glioblastoma Stem-Like Cells to Endothelial Cells under Hypoxia
- Author
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Pamela Ehrenfeld, René Rocha, Ángelo Torres, Rody San Martín, Claudia Quezada, Dellis Rocha, Karina Ojeda, José Ignacio Erices, Ignacio Niechi, and Daniel Uribe
- Subjects
0301 basic medicine ,CD31 ,Male ,Adenosine ,Adenosine A3 Receptor Antagonists ,Neovascularization ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,0302 clinical medicine ,Spectroscopy ,Chemistry ,Cell Differentiation ,General Medicine ,Cell sorting ,A3 adenosine receptor ,Cell Hypoxia ,Computer Science Applications ,Vascular endothelial growth factor ,Endothelial stem cell ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,medicine.symptom ,neovascularization ,glioblastoma stem-like cells ,adenosine ,endothelial cells ,medicine.drug ,endocrine system ,Neovascularization, Physiologic ,Models, Biological ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Vasculogenesis ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Organic Chemistry ,fungi ,Receptor, Adenosine A3 ,Endothelial Cells ,Adenosine A3 receptor ,030104 developmental biology ,Cancer research ,Glioblastoma - Abstract
Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A3 adenosine receptor (A3AR). Moreover, GSCs potentiates the persistent neovascularization in GBM. The aim of this study was to determine if A3AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to Endothelial Cells (ECs) under hypoxia. We evaluated the expression of endothelial cell markers (CD31, CD34, CD144, and vWF) by fluorescence-activated cell sorting (FACS), and vascular endothelial growth factor (VEGF) secretion by ELISA using MRS1220 (A3AR antagonist) under hypoxia. We validate our results using U87MG-GSCs A3AR knockout (GSCsA3-KO). The effect of MRS1220 on blood vessel formation was evaluated in vivo using a subcutaneous GSCs-tumor model. GSCs increased extracellular adenosine production and A3AR expression under hypoxia. Hypoxia also increased the percentage of GSCs positive for endothelial cell markers and VEGF secretion, which was in turn prevented when using MRS1220 and in GSCsA3-KO. Finally, in vivo treatment with MRS1220 reduced tumor size and blood vessel formation. Blockade of A3AR decreases the differentiation of GSCs to ECs under hypoxia and in vivo blood vessel formation.
- Published
- 2018
30. Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists
- Author
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Manuel Antonio González-Gómez, Alberto Coelho, Carlos Carbajales, Hugo Gutiérrez-de-Terán, Olga Caamaño, Jhonny Azuaje, and Eddy Sotelo
- Subjects
Pharmacology ,Drug ,Adenosine A3 Receptor Antagonists ,Drug discovery ,media_common.quotation_subject ,Receptor, Adenosine A3 ,Inflammation ,A3 ADENOSINE RECEPTOR ,Biology ,Neuroprotection ,Molecular Docking Simulation ,Structure-Activity Relationship ,Pyrazines ,Drug Discovery ,medicine ,Humans ,Molecular Medicine ,Structure–activity relationship ,medicine.symptom ,Receptor ,media_common - Abstract
Background: A3AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A3AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A3AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A3AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure–activity and structure–selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.
- Published
- 2015
31. Topological sub-structural molecular design (TOPS-MODE): a useful tool to explore key fragments of human $$\mathbf{A}_{3}$$ A 3 adenosine receptor ligands
- Author
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Liane Saíz-Urra, Pedro Besada, Maria Celeiro, Mª Carmen Terán, Fernanda Borges, Virginia Rivero-Buceta, Marta Teijeira, and Aliuska Morales Helguera
- Subjects
0301 basic medicine ,Quantitative structure–activity relationship ,Stereochemistry ,Topology ,01 natural sciences ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Drug Discovery ,medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Adenosine A3 Receptor Agonists ,Adenosine A3 Receptor Antagonists ,Chemistry ,Drug discovery ,Organic Chemistry ,General Medicine ,Adenosine receptor ,Adenosine ,0104 chemical sciences ,Tops mode ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Function (biology) ,Information Systems ,medicine.drug - Abstract
Adenosine regulates tissue function by activating four G-protein-coupled adenosine receptors (ARs). Selective agonists and antagonists for $$\hbox {A}_{3}$$ ARs have been investigated for the treatment of a variety of immune disorders, cancer, brain, and heart ischemic conditions. We herein present a QSAR study based on a Topological sub-structural molecular design (TOPS-MODE) approach, intended to predict the $$\hbox {A}_{3}$$ ARs of a diverse dataset of 124 (94 training set/ 30 prediction set) adenosine derivatives. The final model showed good fit and predictive capability, displaying 85.1 % of the experimental variance. The TOPS-MODE approach afforded a better understanding and interpretation of the developed model based on the useful information extracted from the analysis of the contribution of different molecular fragments to the affinity.
- Published
- 2015
32. Down-regulation of the A3 adenosine receptor in human mast cells upregulates mediators of angiogenesis and remodeling
- Author
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Ornit Dekel, Ronit Sagi-Eisenberg, and Noam Rudich
- Subjects
Vascular Endothelial Growth Factor A ,EGF Family of Proteins ,Adenosine ,Immunology ,Anti-Inflammatory Agents ,Adenosine A3 Receptor Antagonists ,Down-Regulation ,Immunoglobulin E ,Amphiregulin ,Dexamethasone ,Jurkat Cells ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Humans ,Mast Cells ,Phosphorylation ,RNA, Small Interfering ,Lung ,Molecular Biology ,Interleukin 5 ,Neovascularization, Pathologic ,biology ,Interleukin-6 ,Interleukin-8 ,Receptor, Adenosine A3 ,Mast cell ,Adenosine A3 receptor ,Asthma ,Up-Regulation ,Cell biology ,Interleukin 33 ,Interleukin 10 ,medicine.anatomical_structure ,biology.protein ,Osteopontin ,RNA Interference ,medicine.drug - Abstract
Adenosine activated mast cells have been long implicated in allergic asthma and studies in rodent mast cells have assigned the A3 adenosine receptor (A3R) a primary role in mediating adenosine responses. Here we analyzed the functional impact of A3R activation on genes that are implicated in tissue remodeling in severe asthma in the human mast cell line HMC-1 that shares similarities with lung derived human mast cells. Quantitative real time PCR demonstrated upregulation of IL6, IL8, VEGF, amphiregulin and osteopontin. Moreover, further upregulation of these genes was noted upon the addition of dexamethasone. Unexpectedly, activated A3R down regulated its own expression and knockdown of the receptor replicated the pattern of agonist induced gene upregulation. This study therefore identifies the human mast cell A3R as regulator of tissue remodeling gene expression in human mast cells and demonstrates a heretofore-unrecognized mode of feedback regulation that is exerted by this receptor.
- Published
- 2015
33. Hide and seek: a comparative autoradiographic in vitro investigation of the adenosine A3 receptor
- Author
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Friedrich Girschele, R. Höftberger, Daniela Haeusler, Karem Shanab, I. Leisser, W. Gerdenitsch, L. Grassinger, F. Fuchshuber, W. J. Hörleinsberger, Wolfgang Wadsak, Helmut Spreitzer, Michele R. Hacker, and Markus Mitterhauser
- Subjects
Pathology ,medicine.medical_specialty ,Pyridines ,Periphery ,Adenosine A3 Receptor Antagonists ,Arthritis ,Inflammation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Adenosine A3 receptor ,Receptor ,030304 developmental biology ,0303 health sciences ,MRS1523 ,business.industry ,Receptor, Adenosine A3 ,Nicotinic Acids ,Brain ,Cancer ,General Medicine ,Human brain ,medicine.disease ,Rats ,3. Good health ,Radiography ,medicine.anatomical_structure ,Radiology Nuclear Medicine and imaging ,Autoradiography ,Immunohistochemistry ,Original Article ,CNS ,medicine.symptom ,business ,FE@SUPPY ,030217 neurology & neurosurgery ,Protein Binding - Abstract
Purpose Since the adenosine A3 receptor (A3R) is considered to be of high clinical importance in the diagnosis and treatment of ischaemic conditions (heart and brain), glaucoma, asthma, arthritis, cancer and inflammation, a suitable and selective A3R PET tracer such as [18F]FE@SUPPY would be of high clinical value for clinicians as well as patients. A3R was discovered in the late 1990s, but there is still little known regarding its distribution in the CNS and periphery. Hence, in autoradiographic experiments the distribution of A3R in human brain and rat tissues was investigated and the specific binding of the A3R antagonist FE@SUPPY and MRS1523 compared. Immunohistochemical staining (IHC) experiments were also performed to validate the autoradiographic findings. Methods For autoradiographic competition experiments human post-mortem brain and rat tissues were incubated with [125I]AB-MECA and highly selective compounds to block the other adenosine receptor subtypes. Additionally, IHC was performed with an A3 antibody. Results Specific A3R binding of MRS1523 and FE@SUPPY was found in all rat peripheral tissues examined with the highest amounts in the spleen (44.0 % and 46.4 %), lung (44.5 % and 45.0 %), heart (39.9 % and 42.9 %) and testes (27.4 % and 29.5 %, respectively). Low amounts of A3R were found in rat brain tissues (5.9 % and 5.6 %, respectively) and human brain tissues (thalamus 8.0 % and 9.1 %, putamen 7.8 % and 8.2 %, cerebellum 6.0 % and 7.8 %, hippocampus 5.7 % and 5.6 %, caudate nucleus 4.9 % and 6.4 %, cortex 4.9 % and 6.3 %, respectively). The outcome of the A3 antibody staining experiments complemented the results of the autoradiographic experiments. Conclusion The presence of A3R protein was verified in central and peripheral tissues by autoradiography and IHC. The specificity and selectivity of FE@SUPPY was confirmed by direct comparison with MRS1523, providing further evidence that [18F]FE@SUPPY may be a suitable A3 PET tracer for use in humans.
- Published
- 2015
34. Lipopolysaccharide-induced serotonin transporter up-regulation involves PKG-I and p38MAPK activation partially through A3 adenosine receptor
- Author
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Guanhua Du, Zhizhen Qin, Dan Zhou, Shou-Bao Wang, Rui Zhao, Xiuying Yang, Li Zhang, Zhonglin Huang, and Xiao-yu Bai
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Lipopolysaccharides ,Serotonin ,medicine.medical_specialty ,Health (social science) ,Lipopolysaccharide ,p38 mitogen-activated protein kinases ,Blotting, Western ,Adenosine A3 Receptor Antagonists ,Fluorescent Antibody Technique ,Biology ,Pharmacology ,Nitric Oxide ,Models, Biological ,p38 Mitogen-Activated Protein Kinases ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Receptor ,Protein kinase A ,Cells, Cultured ,Serotonin transporter ,Cyclic GMP-Dependent Protein Kinase Type I ,Serotonin Plasma Membrane Transport Proteins ,Activator (genetics) ,Kinase ,Cell Membrane ,Receptor, Adenosine A3 ,General Medicine ,Up-Regulation ,Endocrinology ,chemistry ,biology.protein ,Calcium - Abstract
Serotonin transporter (SERT) is a critical determinant of synaptic serotonin (5-hydroxytryptamine, 5-HT) inactivation which plays a critical role in the pathology of depression and other mood disorders. Lipopolysaccharide (LPS), a potent activator of the inflammatory system, has been reported to cause depression symptoms by the modulation of SERT in vivo and in vitro. This study is aimed to investigate the underlying mechanism of LPS-induced SERT modulation. The 4-(4-(dimethylamino) styryl)-N-methylpyridinium iodide (ASP) assay was used to detect dynamic 5-HT uptake as read out of SERT activities in RBL-2H3 cells, and cytosol Ca(2+) concentrations ([Ca(2+)]i) and nitric oxide (NO) were examined. Using specific cyclic GMP-dependent protein kinase type I (PKG-I), p38 mitogen-activated protein kinases (p38MAPK) and A3 adenosine receptor (A3AR) inhibitors, SERT expression was evaluated by western blot and immunofluorescence analysis. Results showed that 24 h treatment with LPS stimulated 5-HT transport and up-regulate plasma membrane distribution of SERT in RBL-2H3 cells. LPS treatment increased NO and [Ca(2+)]i, and led to significant increases in levels of phosphorylated calcium/calmodulin-dependent protein kinase type II (CaMK-II), inducible NOS (iNOS) and PKG-I as well as active p38 MAPK. Moreover, PKG-I inhibitor KT5823 or p38MAPK inhibitor SB203580 respectively impaired SERT activation and transposition to plasma membrane by LPS. Notably, A3 adenosine receptor inhibitor MRS1191 also hindered SERT stimulation by LPS. In conclusion, LPS-induced 5-HT uptake and transposition to plasma membrane of SERT in RBL-2H3 cells involves CaMK-II/iNOS/PKG-I and p38 MAPK activation, which may be partially mediated by A3 adenosine receptor activation. This finding provides a novel insight into the interrelationship between LPS and depression.
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- 2015
35. Anticancer and antimetastatic effects of cordycepin, an active component of Cordyceps sinensis
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Kazuki Nakamura, Noriko Yoshikawa, and Kazumasa Shinozuka
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Kupffer Cells ,Adenosine A3 Receptor Antagonists ,Antineoplastic Agents ,Pharmacology ,Models, Biological ,chemistry.chemical_compound ,Adenosine A3 Receptor Agonists ,GSK-3 ,Cell Line, Tumor ,Antimetastatic Agent ,medicine ,Animals ,Humans ,Medicine, Chinese Traditional ,Neoplasm Metastasis ,Adenosine A3 receptor ,Antimetastasis ,Cordycepin (3′-deoxyadenosine) ,Cordyceps ,Deoxyadenosines ,biology ,Cordycepin ,Plant Extracts ,Chemistry ,lcsh:RM1-950 ,Receptor, Adenosine A3 ,Atherosclerosis ,biology.organism_classification ,Adenosine ,lcsh:Therapeutics. Pharmacology ,Methotrexate ,Anticancer ,Cancer cell ,Molecular Medicine ,Drug Therapy, Combination ,Water extract of Cordyceps sinensis (WECS) ,Adenosine Deaminase Inhibitor ,Pentostatin ,Phytotherapy ,Signal Transduction ,medicine.drug - Abstract
Cordyceps sinensis , a fungus that parasitizes on the larva of Lepidoptera, has been used as a valued traditional Chinese medicine. We investigated the effects of water extracts of Cordyceps sinensis (WECS), and particularly focused on its anticancer and antimetastatic actions. Based on in vitro studies, we report that WECS showed an anticancer action, and this action was antagonized by an adenosine A 3 receptor antagonist. Moreover, this anticancer action of WECS was promoted by an adenosine deaminase inhibitor. These results suggest that one of the components of WECS with an anticancer action might be an adenosine or its derivatives. Therefore, we focused on cordycepin (3′-deoxyadenosine) as one of the active ingredients of WECS. According to our experiments, cordycepin showed an anticancer effect through the stimulation of adenosine A 3 receptor, followed by glycogen synthase kinase (GSK)-3β activation and cyclin D 1 suppression. Cordycepin also showed an antimetastatic action through inhibiting platelet aggregation induced by cancer cells and suppressing the invasiveness of cancer cells via inhibiting the activity of matrix metalloproteinase (MMP)-2 and MMP-9, and accelerating the secretion of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 from cancer cells. In conclusion, cordycepin, an active component of WECS, might be a candidate anticancer and antimetastatic agent.
- Published
- 2015
36. Structure-Affinity Relationships and Structure-Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A(3) Receptor Antagonists
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Eelke B. Lenselink, Jacobus P. D. van Veldhoven, Tirsa T. van Duijl, Laura H. Heitman, Adriaan P. IJzerman, Boaz J. Kuiper, Ellen Paasman, Lizi Xia, and Wessel A.C. Burger
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0301 basic medicine ,Purine ,Stereochemistry ,Kinetics ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,Drug Discovery ,Animals ,Humans ,Receptor ,Drug discovery ,Chemistry ,Receptor, Adenosine A3 ,Adenosine A3 receptor ,Affinities ,Receptor–ligand kinetics ,Molecular Docking Simulation ,030104 developmental biology ,Biochemistry ,Purines ,Molecular Medicine - Abstract
We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A3 receptor (hA3R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hA3R antagonists with very short residence time (RT) at the receptor (2.2 min for 5) and much longer RTs (e.g., 376 min for 27 or 391 min for 31). Two representative antagonists (5 and 27) were tested in [35S]GTPγS binding assays, and their RTs appeared correlated to their (in)surmountable antagonism. From a kon-koff-KD kinetic map, we divided the antagonists into three subgroups, providing a possible direction for the further development of hA3R antagonists. Additionally, we performed a computational modeling study that sheds light on the crucial receptor interactions, dictating the compounds' binding kinetics. Knowledge of target binding kinetics appears useful for developing and triaging new hA3R antagonists in the early phase of drug discovery.
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- 2017
37. Polypharmacology of N
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Jinha, Yu, Seyeon, Ahn, Hee Jin, Kim, Moonyoung, Lee, Sungjin, Ahn, Jungmin, Kim, Sun Hee, Jin, Eunyoung, Lee, Gyudong, Kim, Jae Hoon, Cheong, Kenneth A, Jacobson, Lak Shin, Jeong, and Minsoo, Noh
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Male ,Adenosine ,Polypharmacology ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,Ligands ,Article ,Cell Line ,Diabetes Mellitus, Experimental ,Mice, Inbred C57BL ,PPAR gamma ,Mice ,Adenosine A3 Receptor Agonists ,Animals ,Humans ,Hypoglycemic Agents ,Adiponectin ,PPAR delta ,Insulin Resistance - Abstract
A3 adenosine receptor (AR) ligands including A3 AR agonist, N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (1a, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, 1a significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A3 AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A3 AR pathway may not be directly involved in the adiponectin promoting activity. In a target deconvolution study, their adiponectin-promoting activity was significantly correlated to their binding activity to both peroxisome proliferator activated receptor (PPAR) γ and PPARδ. They functioned as both PPARγ partial agonists and PPARδ antagonists. In the diabetic mouse model, 1a and its structural analogues A3 AR antagonists significantly decreased the serum levels of glucose and triglyceride, supporting their antidiabetic potential. These findings indicate that the polypharmacophore of these compounds may provide therapeutic insight into their multipotent efficacy against various human diseases.
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- 2017
38. Effect of Nitrogen Atom Substitution in A
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Jhonny, Azuaje, Willem, Jespers, Vicente, Yaziji, Ana, Mallo, María, Majellaro, Olga, Caamaño, María I, Loza, María I, Cadavid, José, Brea, Johan, Åqvist, Eddy, Sotelo, and Hugo, Gutiérrez-de-Terán
- Subjects
Binding Sites ,Nitrogen ,Receptor, Adenosine A3 ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Molecular Docking Simulation ,Structure-Activity Relationship ,Cricetulus ,Pyrimidines ,Drug Design ,Acetamides ,Animals ,Computer-Aided Design ,Humans - Abstract
We report the first family of 2-acetamidopyridines as potent and selective A
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- 2017
39. Exploring the Role of N
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Riccardo, Petrelli, Mirko, Scortichini, Sonja, Kachler, Serena, Boccella, Carmen, Cerchia, Ilaria, Torquati, Fabio, Del Bello, Daniela, Salvemini, Ettore, Novellino, Livio, Luongo, Sabatino, Maione, Kenneth A, Jacobson, Antonio, Lavecchia, Karl-Norbert, Klotz, and Loredana, Cappellacci
- Subjects
Models, Molecular ,Analgesics ,Adenosine ,Receptor, Adenosine A1 ,Receptor, Adenosine A3 ,Receptors, Purinergic P1 ,Adenosine A3 Receptor Antagonists ,Acute Pain ,Article ,Adenosine A1 Receptor Agonists ,Mice ,Purinergic P1 Receptor Antagonists ,Purinergic P1 Receptor Agonists ,Animals ,Humans - Abstract
Structural determinants of affinity of N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N6-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR. All N6-substituted-5′-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA3AR but agonists at the rA3AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A3AR antagonist blocked and A3AR agonist strongly potentiated). N6-Methyl-5′-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A1AR and A3AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.
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- 2017
40. Determination and validation of LJ-2698, a potent human A
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Jae-Young, Lee, Ju-Hwan, Park, Ki-Taek, Kim, Jinha, Yu, Pramod K, Sahu, Naewon, Kang, Hyeon-Jong, Shin, Min-Hwan, Kim, Ji-Su, Kim, In-Soo, Yoon, Lak Shin, Jeong, and Dae-Duk, Kim
- Subjects
Male ,Spectrometry, Mass, Electrospray Ionization ,Thionucleosides ,Dose-Response Relationship, Drug ,Adenosine A3 Receptor Antagonists ,Administration, Oral ,Reproducibility of Results ,Rats, Sprague-Dawley ,Limit of Detection ,Tandem Mass Spectrometry ,Calibration ,Animals ,Administration, Intravenous ,Chromatography, Liquid - Abstract
LJ-2698, a highly potent human A
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- 2017
41. Role and Function of A
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Annalisa, Ravani, Fabrizio, Vincenzi, Alessandra, Bortoluzzi, Melissa, Padovan, Silvia, Pasquini, Stefania, Gessi, Stefania, Merighi, Pier Andrea, Borea, Marcello, Govoni, and Katia, Varani
- Subjects
Male ,rheumatoid arthritis ,Adenosine ,Adenosine A2 Receptor Agonists ,Receptor, Adenosine A2A ,Adenosine A3 Receptor Antagonists ,Article ,Arthritis, Rheumatoid ,Adenosine A3 Receptor Agonists ,Phenethylamines ,ankylosing spondylitis ,Humans ,Spondylitis, Ankylosing ,Lymphocytes ,RNA, Messenger ,psoriatic arthritis ,Arthritis, Psoriatic ,Receptor, Adenosine A3 ,NF-kappa B ,Middle Aged ,adenosine receptors ,Adenosine A2 Receptor Antagonists ,Kinetics ,Pyrimidines ,inflammation ,Case-Control Studies ,Cytokines ,Pyrazoles ,Female ,Matrix Metalloproteinase 3 ,Matrix Metalloproteinase 1 - Abstract
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.
- Published
- 2017
42. Adenosine and adenosine receptors in the immunopathogenesis and treatment of cancer
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Mohammad Hojjat-Farsangi, Enayat Anvari, Ghasem Ghalamfarsa, Sahar Raoofi Mohseni, Mohammad Hossein Kazemi, Farhad Jadidi-Niaragh, and Hamed Mohammadi
- Subjects
0301 basic medicine ,Adenosine ,Adenosine A2 Receptor Agonists ,Physiology ,Clinical Biochemistry ,Adenosine A3 Receptor Antagonists ,Pharmacology ,Biology ,Adenosine A1 Receptor Antagonists ,GPI-Linked Proteins ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,Adenosine Triphosphate ,Adenosine A3 Receptor Agonists ,Antigens, CD ,Neoplasms ,medicine ,Animals ,Humans ,5'-Nucleotidase ,Tumor microenvironment ,Receptor, Adenosine A1 ,Receptors, Adenosine A2 ,Apyrase ,Receptor, Adenosine A3 ,Cell Biology ,Purinergic signalling ,Adenosine A3 receptor ,Adenosine receptor ,Adenosine A1 Receptor Agonists ,Adenosine A2 Receptor Antagonists ,030104 developmental biology ,chemistry ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Tumor Escape ,Adenosine triphosphate ,medicine.drug ,Signal Transduction - Abstract
Tumor cells overcome anti-tumor responses in part through immunosuppressive mechanisms. There are several immune modulatory mechanisms. Among them, adenosine is an important factor which is generated by both cancer and immune cells in tumor microenvironment to suppress anti-tumor responses. Two cell surface expressed molecules including CD73 and CD39 catalyze the generation of adenosine from adenosine triphosphate (ATP). The generation of adenosine can be enhanced under metabolic stress like tumor hypoxic conditions. Adenosine exerts its immune regulatory functions through four different adenosine receptors (ARs) including A1, A2A, A2B, and A3 which are expressed on various immune cells. Several studies have indicated the overexpression of adenosine generating enzymes and ARs in various cancers which was correlated with tumor progression. Since the signaling of ARs enhances tumor progression, their manipulation can be promising therapeutic approach in cancer therapy. Accordingly, several agonists and antagonists against ARs have been designed for cancer therapy. In this review, we will try to clarify the role of different ARs in the immunopathogenesis, as well as their role in the treatment of cancer.
- Published
- 2017
43. Retinal A2A and A3 adenosine receptors modulate the components of the rat electroretinogram
- Author
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Gudmundur Jonsson and Thor Eysteinsson
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Adenosine ,Adenosine A2 Receptor Agonists ,Receptor, Adenosine A2A ,Physiology ,Adenosine A3 Receptor Antagonists ,Dark Adaptation ,Biology ,Retina ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Adenosine A3 Receptor Agonists ,Internal medicine ,Electroretinography ,medicine ,Animals ,Scotopic vision ,medicine.diagnostic_test ,Receptor, Adenosine A3 ,Retinal ,Adenosine receptor ,Sensory Systems ,Adenosine A2 Receptor Antagonists ,Rats ,030104 developmental biology ,Endocrinology ,chemistry ,Intravitreal Injections ,Female ,Erg ,Photic Stimulation ,030217 neurology & neurosurgery ,medicine.drug ,Photopic vision - Abstract
Adenosine is a neuromodulator present in various areas of the central nervous system, including the retina. Adenosine may serve a neuroprotective role in the retina, based on electroretinogram (ERG) recordings from the rat retina. Our purpose was to assess the role of A2A and A3 adenosine receptors in the generation and modulation of the rat ERG. The flash ERG was recorded with corneal electrodes from Sprague Dawley rats. Agonists and antagonists for A2A and A3 receptors, and adenosine were injected (5 µl) into the vitreous. The effects on the components of the single flash scotopic and photopic ERGs were examined, and ERG flicker. Adenosine (0.5 mM) increased the mean amplitudes of the scotopic ERG a-waves (68 ± 8 to 97 ± 14 µV, P = 0.042), and b-waves (236 ± 38 µV to 305 ± 42 µV). A2A agonist CGS21680 (2 mM) reduced the mean amplitude of the ERG b-wave, from 298 ± 21 µV in response to the brightest stimulus to 212 ± 19 µV (P = 0.005), and mean scotopic oscillatory potentials (OPs) from 100 ± 9 µV to 47 ± 11 µV (P = 0.023). ZM241385 [4 mM], an A2A antagonist, decreased the scotopic b-wave of the ERG. A3 agonist 2-CI-IB-MECA (0.5 mM) increased the a-wave, while decreasing the scotopic and photopic ERG b-waves, and the scotopic OPs. A3 antagonist VUF5574 (1 mM) increased the mean amplitude of the scotopic a-wave (66 ± 8 to 140 ± 29 µV, P = 0.046) and b-wave (224 ± 20 to 312 ± 39 µV, P = 0.0037). No significant effects on ERG flicker were found. We conclude that retinal neurons containing A2A and/or A3 adenosine receptors contribute to the generation of the ERG a- and b-waves and OPs.
- Published
- 2017
44. Synthesis and Anti-Renal Fibrosis Activity of Conformationally Locked Truncated 2-Hexynyl-N6-Substituted-(N)-Methanocarba-nucleosides as A3 Adenosine Receptor Antagonists and Partial Agonists
- Author
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Jakyung Yoo, Khai Phan, Inah Hwang, Zhan Guo Gao, Hunjoo Ha, Sun Choi, Akshata Nayak, Girish Chandra, Kyunglim Kim, Steven M. Moss, Minghua Cui, Pramod K. Sahu, Kuldeep K. Roy, Kenneth A. Jacobson, Lak Shin Jeong, Hea Ok Kim, Xiyan Hou, and Yoonji Lee
- Subjects
Agonist ,medicine.drug_class ,Stereochemistry ,Molecular Conformation ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Partial agonist ,Article ,Cricetulus ,Downregulation and upregulation ,Adenosine A3 Receptor Agonists ,Cricetinae ,Drug Discovery ,medicine ,Animals ,Humans ,biology ,Chemistry ,Chinese hamster ovary cell ,Nucleosides ,biology.organism_classification ,Affinities ,Fibrosis ,HEK293 Cells ,Molecular Medicine ,Kidney Diseases ,Hydrophobic and Hydrophilic Interactions - Abstract
Truncated N(6)-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N(6) and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N(6)-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with Ki values of 7.8-16.0 nM. N(6)-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
- Published
- 2014
45. Synthesis of Novel Pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective Adenosine A3Receptor Antagonists
- Author
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Christa E. Müller, Raghuramarao Akkinepally, Veeraswamy Banda, Kurumurthy Chavva, Christin Vielmuth, Santhosh Kumar Gautham, Meryem Köse, Narsaiah Banda, Balakumar Chandrasekaran, Sambasivarao Pillalamarri, Raghuprasad Mylavaram, and Shanthanrao Pamulaparthy
- Subjects
chemistry.chemical_compound ,Adenosine A3 Receptor Antagonists ,Trifluoromethyl ,chemistry ,Pyrimidine ,Stereochemistry ,Drug Discovery ,Pharmaceutical Science ,Receptor ,Adenosine receptor - Abstract
A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3-cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A3 receptors, with Ki values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes.
- Published
- 2013
46. Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold
- Author
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David Rodríguez, Eddy Sotelo, José Brea, Vicente Yaziji, María Isabel Cadavid, Xerardo García-Mera, María Isabel Loza, Alberto Coelho, Abdelaziz El Maatougui, and Hugo Gutiérrez-de-Terán
- Subjects
Models, Molecular ,Pharmacology ,Scaffold ,Binding Sites ,Adenosine A3 Receptor Antagonists ,Chemistry ,Stereochemistry ,Organic Chemistry ,Substitution (logic) ,General Medicine ,Anisoles ,A3 ADENOSINE RECEPTOR ,Adenosine receptor ,Combinatorial chemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pyrimidines ,Acetamides ,Drug Discovery ,Humans ,Computer Simulation ,Selectivity ,Acetamide - Abstract
The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A3 adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (Ki on A3 AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A3AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series.© 2012 Elsevier Masson SAS. All rights reserved.
- Published
- 2013
47. Interaction of SSR161421, a novel specific adenosine A3 receptor antagonist with adenosine A3 receptor agonists both in vitro and in vivo
- Author
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Géza Timári, Michel Finet, Peter Aranyi, Anne-Marie Galzin, Vargane Szeredi Judit, Sandor Batori, Kinga Boer, Tibor Szabó, Zoltán Kapui, Katalin Urban-Szabo, Endre Mikus, and Katalin Gerber
- Subjects
Male ,Adenosine ,medicine.drug_class ,Adenosine A3 Receptor Antagonists ,CHO Cells ,Pharmacology ,Inhibitory Concentration 50 ,Mice ,Plasma ,Adenosine A1 receptor ,Cricetulus ,Adenosine A3 Receptor Agonists ,Cricetinae ,Cyclic AMP ,medicine ,Animals ,Edema ,Humans ,Drug Interactions ,Chemistry ,Receptors, Purinergic P1 ,Purinergic signalling ,Adenosine A3 receptor ,Receptor antagonist ,Adenosine receptor ,Disease Models, Animal ,Benzamides ,Aminoquinolines ,Adenosine A2B receptor ,Histamine ,medicine.drug - Abstract
A novel adenosine A 3 receptor antagonist (SSR161421) was characterized by both receptor binding assays and pharmacological tests. Binding studies on cloned human adenosine receptors showed that SSR161421 has high affinity for adenosine hA 3 receptors ( K i =0.37 nM) with at least 1000-fold selectivity compared to hA 1 , hA 2A and hA 2B receptors. The receptor antagonist nature of SSR161421 was determined in a functional study on Chinese hamster ovarian cells (CHO) cells expressing human adenosine A 3 receptors. SSR161421 competitively antagonized the effect of 2-chloro- N 6-(3-iodobenzyl)-adenosine-5′- N -methylcarboxamide (Cl-IB-MECA) on cAMP production with a pA2 value in a luciferase reporter gene construct. In mice, intravenously administered SSR161421 inhibited the N 6-(4-aminobenzyl)-adenosine-5′- N -methyl-uronamide dihydrochloride (AB-MECA) induced increase in plasma histamine levels (ED 50 =2.0 mg/kg) and the Cl-IB-MECA evoked plasma extravasation (ID 50 =2.9 mg/kg) and oedema formation (ID 50 =4.6 mg/kg) in mouse ear.
- Published
- 2013
48. Targeting adenosine receptors with coumarins: synthesis and binding activities of amide and carbamate derivatives
- Author
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Sonja Kachler, Lourdes Santana, Karl-Norbert Klotz, Fernanda Borges, Eugenio Uriarte, Alexandra Gaspar, and Maria João Matos
- Subjects
Carbamate ,Receptor, Adenosine A2A ,Stereochemistry ,medicine.medical_treatment ,Substituent ,Adenosine A3 Receptor Antagonists ,Pharmaceutical Science ,CHO Cells ,Adenosine A1 Receptor Antagonists ,Hydroxylation ,Binding, Competitive ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Coumarins ,Cricetinae ,Amide ,medicine ,Animals ,Humans ,Moiety ,Pharmacology ,Receptor, Adenosine A1 ,Receptor, Adenosine A3 ,Receptors, Purinergic P1 ,Coumarin ,Amides ,Adenosine receptor ,Recombinant Proteins ,Adenosine A2 Receptor Antagonists ,Kinetics ,chemistry ,Radioligand binding ,Carbamates ,Selectivity - Abstract
Objectives With the aim of finding the structural features governing binding activity and selectivity against adenosine receptors (ARs), several 3-subtituted coumarins with amide (compounds 3–6) and carbamate (7–9) functions were synthesized. To study its possible influence on the binding activity and selectivity, a hydroxyl substituent was also introduced at position 4 of the coumarin moiety. Methods A new series of coumarins (3–9) were synthesized and evaluated by radioligand binding studies towards ARs. Key findings None of the 4-hydroxy derivatives (4, 8 and 9) showed binding affinity for any of the ARs. None of the compounds interacted with the hA2B AR (Ki > 100 000 nm). Compounds 3, 5, 6 and 7 had different activity profiles with dissimilar binding affinity and selectivity towards human A1, A2A and A3 ARs. Conclusions The most remarkable derivative is compound 7, which presents the best affinity and selectivity for the A3 adenosine receptor (Ki = 5500 nm).
- Published
- 2012
49. Ligand-, Structure-and Pharmacophore-based Molecular Fingerprints: A Case Study on Adenosine A1, A2A, A2B, and A3 Receptor Antagonists
- Author
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Raimund Mannhold, Francesco Sirci, Laura Goracci, Jacqueline E. van Muijlwijk-Koezen, David Rodríguez, Hugo Gutiérrez-de-Terán, Chemistry and Pharmaceutical Sciences, and AIMMS
- Subjects
Models, Molecular ,SDG 16 - Peace ,Protein Conformation ,Stereochemistry ,Adenosine A3 Receptor Antagonists ,Adenosine A1 Receptor Antagonists ,Molecular Dynamics Simulation ,Ligands ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Physical and Theoretical Chemistry ,Receptor ,Chemistry ,SDG 16 - Peace, Justice and Strong Institutions ,Receptors, Purinergic P1 ,Ligand (biochemistry) ,Adenosine receptor ,Adenosine ,Justice and Strong Institutions ,Adenosine A2 Receptor Antagonists ,Computer Science Applications ,Pharmacophore ,Human species ,medicine.drug - Abstract
FLAP fingerprints are applied in the ligand-, structure- and pharmacophore-based mode in a case study on antagonists of all four adenosine receptor (AR) subtypes. Structurally diverse antagonist collections with respect to the different ARs were constructed by including binding data to human species only. FLAP models well discriminate “active” (=highly potent) from “inactive” (=weakly potent) AR antagonists, as indicated by enrichment curves, numbers of false positives, and AUC values. For all FLAP modes, model predictivity slightly decreases as follows: A2BR > A2AR > A3R > A1R antagonists. General performance of FLAP modes in this study is: ligand- > structure- > pharmacophore- based mode. We also compared the FLAP performance with other common ligand- and structure-based fingerprints. Concerning the ligand-based mode, FLAP model performance is superior to ECFP4 and ROCS for all AR subtypes. Although focusing on the early first part of the A2A, A2B and A3 enrichment curves, ECFP4 and ROCS still retain a satisfactory retrieval of actives. FLAP is also superior when comparing the structure-based mode with PLANTS and GOLD. In this study we applied for the first time the novel FLAPPharm tool for pharmacophore generation. Pharmacophore hypotheses, generated with this tool, convincingly match with formerly published data. Finally, we could demonstrate the capability of FLAP models to uncover selectivity aspects although single AR subtype models were not trained for this purpose.
- Published
- 2012
50. Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A
- Author
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Daniela, Poli, Matteo, Falsini, Flavia, Varano, Marco, Betti, Katia, Varani, Fabrizio, Vincenzi, Anna Maria, Pugliese, Felicita, Pedata, Diego, Dal Ben, Ajiroghene, Thomas, Ilaria, Palchetti, Francesca, Bettazzi, Daniela, Catarzi, and Vittoria, Colotta
- Subjects
Receptor, Adenosine A2A ,Receptor, Adenosine A3 ,Imidazoles ,Adenosine A3 Receptor Antagonists ,Hippocampus ,Brain Ischemia ,Rats ,Molecular Docking Simulation ,Chromosome Pairing ,Purinergic P1 Receptor Antagonists ,Drug Design ,Pyrazines ,Animals ,Humans ,Amines - Abstract
The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A
- Published
- 2016
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