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Adenosine receptor inhibitor in Parkinson's disease

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https://www.readbyqxmd.com/read/29792714/docking-screens-for-dual-inhibitors-of-disparate-drug-targets-for-parkinson-s-disease
#1
Mariama Jaiteh, Alexey Zeifman, Marcus Saarinen, Per Svenningsson, José M Brea, Maria Isabel Loza, Jens Carlsson
Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B)...
May 24, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29690896/marine-derived-protein-kinase-inhibitors-for-neuroinflammatory-diseases
#2
REVIEW
Chong Ning, Hui-Min David Wang, Rong Gao, Yu-Chia Chang, Fengqing Hu, Xianjun Meng, Shi-Ying Huang
Neuroinflammation is primarily characterized by overexpression of proinflammatory mediators produced by glial activation or immune cell infiltration. Several kinases have been shown to be critical mediators in neuroinflammation. One of the largest groups of kinases is protein kinases, which have been the second most studied group of drug targets after G-protein-coupled receptors. Thus far, most of the approved kinase inhibitor drugs are adenosine triphosphate-competitive inhibitors with various off-target liabilities because of cross-reactivities; however, marine-derived compounds provide opportunities for discovering allosteric kinase inhibitors...
April 24, 2018: Biomedical Engineering Online
https://www.readbyqxmd.com/read/29570862/medical-and-surgical-management-of-advanced-parkinson-s-disease
#3
REVIEW
Angelo Antonini, Elena Moro, Clecio Godeiro, Heinz Reichmann
Advanced Parkinson's disease is characterized by the presence of motor fluctuations, various degree of dyskinesia, and disability with functional impact on activities of daily living and independence. Therapeutic management aims to extend levodopa benefit while minimizing motor complications and includes, in selected cases, the implementation of drug infusion and surgical techniques. In milder forms of motor complications, these can often be controlled with manipulation of levodopa dose and the introduction of supplemental therapies such as catechol-O-methyl transferase inhibitors, monoamine oxidase B inhibitors, and dopamine agonists including apomorphine...
March 23, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29559851/role-of-plant-derived-alkaloids-and-their-mechanism-in-neurodegenerative-disorders
#4
REVIEW
Ghulam Hussain, Azhar Rasul, Haseeb Anwar, Nimra Aziz, Aroona Razzaq, Wei Wei, Muhammad Ali, Jiang Li, Xiaomeng Li
Neurodegenerative diseases are conventionally demarcated as disorders with selective loss of neurons. Conventional as well as newer molecules have been tested but they offer just symptomatic advantages along with abundant side effects. The discovery of more compelling molecules that can halt the pathology of these diseases will be considered as a miracle of present time. Several synthetic compounds are available but they may cause several other health issues. Therefore, natural molecules from the plants and other sources are being discovered to replace available medicines...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29516413/interplay-between-adenosine-receptor-antagonist-and-cyclooxygenase-inhibitor-in-haloperidol-induced-extrapyramidal-effects-in-mice
#5
Devinder Arora, Jayesh Mudgal, Madhavan Nampoothiri, Sanchari Basu Mallik, Manas Kinra, Susan Hall, Shailendra Anoopkumar-Dukie, Gary D Grant, Chamallamudi Mallikarjuna Rao
Antipsychotic drugs are the mainstay of psychotic disorders. The 'typical' antipsychotic agents are commonly employed for the positive symptoms of schizophrenia, though at an expense of extrapyramidal side effects (EPS). In the present study, we employed haloperidol (HP)-induced catalepsy model in mice to evaluate the role of adenosine receptor antagonist and cyclooxygenase (COX) enzyme inhibitor in the amelioration of EPS. HP produced a full blown catalepsy, akinesia and a significant impairment in locomotion and antioxidant status...
March 7, 2018: Metabolic Brain Disease
https://www.readbyqxmd.com/read/29508924/a-selective-phosphodiesterase-10a-inhibitor-reduces-l-dopa-induced-dyskinesias-in-parkinsonian-monkeys
#6
Goichi Beck, Shunsuke Maehara, Phat Ly Chang, Stella M Papa
BACKGROUND: Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia...
March 6, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28842709/the-parkinson-s-disease-associated-gpr37-receptor-interacts-with-striatal-adenosine-a2a-receptor-controlling-its-cell-surface-expression-and-function-in-vivo
#7
Xavier Morató, Rafael Luján, Marc López-Cano, Jorge Gandía, Igor Stagljar, Masahiko Watanabe, Rodrigo A Cunha, Víctor Fernández-Dueñas, Francisco Ciruela
G protein-coupled receptor 37 (GPR37) is an orphan receptor associated to Parkinson's disease (PD) neuropathology. Here, we identified GPR37 as an inhibitor of adenosine A2A receptor (A2AR) cell surface expression and function in vivo. In addition, we showed that GPR37 and A2AR do oligomerize in the striatum. Thus, a close proximity of GPR37 and A2AR at the postsynaptic level of striatal synapses was observed by double-labelling post-embedding immunogold detection. Indeed, the direct receptor-receptor interaction was further substantiated by proximity ligation in situ assay...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28629145/synthesis-and-evaluation-of-phenylxanthine-derivatives-as-potential-dual-a2ar-antagonists-mao-b-inhibitors-for-parkinson-s-disease
#8
Xuebao Wang, Chao Han, Yong Xu, Kaiqi Wu, Shuangya Chen, Mangsha Hu, Luyao Wang, Yun Ye, Faqing Ye
The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson's disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo...
June 17, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28093976/chemoinformatics-profiling-of-the-chromone-nucleus-as-a-mao-b-a2aar-dual-binding-scaffold
#9
Maykel Cruz-Monteagudo, Fernanda Borges, M Natalia D S Cordeiro, Aliuska Morales Helguera, Eduardo Tejera, Cesar Paz-Y-Mino, Aminael Sanchez-Rodriguez, Yunier Perera-Sardina, Yunierkis Perez-Castillo
BACKGROUND: In the context of the current drug discovery efforts to find disease modifying therapies for Parkinson's disease (PD) the current single target strategy has proved inefficient. Consequently, the search for multi-potent agents is attracting more and more attention due to the multiple pathogenetic factors implicated in PD. Multiple evidences points to the dual inhibition of the monoamine oxidase B (MAO-B), as well as adenosine A2A receptor (A2AAR) blockade, as a promising approach to prevent the neurodegeneration involved in PD...
November 14, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28067172/fusing-docking-scoring-functions-improves-the-virtual-screening-performance-for-discovering-parkinson-39-s-disease-dual-target-ligands
#10
Yunierkis Perez-Castillo, Aliuska Morales Helguera, M Natalia D S Cordeiro, Eduardo Tejera, Cesar Paz-Y-Mino, Aminael Sanchez-Rodriguez, Fernanda Borges, Maykel Cruz-Monteagudo
BACKGROUND: Virtual methodologies have become essential components of the drug discovery pipeline. Specifically, structure-based drug design methodologies exploit the 3D structure of molecular targets to discover new drug candidates through molecular docking. Recently, dual target ligands of the Adenosine A2A Receptor and Monoamine Oxidase B enzyme have been proposed as effective therapies for the treatment of Parkinson's disease. METHODS: In this paper we propose a structure-based methodology, which is extensively validated, for the discovery of dual Adenosine A2A Receptor/Monoamine Oxidase B ligands...
November 14, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28062949/can-cyclic-nucleotide-phosphodiesterase-inhibitors-be-drugs-for-parkinson-s-disease
#11
REVIEW
Dominic Ngima Nthenge-Ngumbau, Kochupurackal P Mohanakumar
Parkinson's disease (PD) has no known cure; available therapies are only capable of offering temporary, symptomatic relief to the patients. Varied therapeutic strategies that are clinically used for PD are pharmacological therapies including dopamine replacement therapies (with or without adjuvant), postsynaptic dopamine receptor stimulation, dopamine catabolism inhibitors and also anticholinergics. Surgical therapies like deep brain stimulation and ablative surgical techniques are also employed. Phosphodiesterases (PDEs) are enzymes that degrade the phosphodiester bond in the second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)...
January 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/27658798/8-substituted-1-3-dimethyltetrahydropyrazino-2-1-f-purinediones-water-soluble-adenosine-receptor-antagonists-and-monoamine-oxidase-b-inhibitors
#12
Andreas Brunschweiger, Pierre Koch, Miriam Schlenk, Muhammad Rafehi, Hamid Radjainia, Petra Küppers, Sonja Hinz, Felipe Pineda, Michael Wiese, Jörg Hockemeyer, Jag Heer, Frédéric Denonne, Christa E Müller
Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1 ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs...
November 1, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27230697/nondopaminergic-treatments-for-parkinson-s-disease-current-and-future-prospects
#13
REVIEW
Maria Eliza Freitas, Susan H Fox
Parkinson's disease is primarily caused by dysfunction of dopaminergic neurons, however, nondopaminergic (ND) systems are also involved. ND targets are potentially useful to reduce doses of levodopa or to treat nonlevodopa-responsive symptoms. Recent studies have investigated the role of ND drugs for motor and nonmotor symptoms. Adenosine A2A receptor antagonists, mixed inhibitors of sodium/calcium channels and monoamine oxidase-B have recently been found to improve motor fluctuations. N-methyl-d-aspartate receptor antagonists and serotonin 5HT1B receptor agonists demonstrated benefit in levodopa-induced dyskinesia...
June 2016: Neurodegenerative Disease Management
https://www.readbyqxmd.com/read/27186120/investigational-agents-in-the-treatment-of-parkinson-s-disease-focus-on-safinamide
#14
REVIEW
Naveed M Malek, Donald G Grosset
The authors review management issues in Parkinson's disease (PD) and provide an overview of the current pharmacological management strategies, with a specific focus on safinamide. Current therapeutic management of PD largely involves strategies to optimize the replacement of deficient dopamine, using levodopa, dopamine agonists, and inhibitors of dopamine-metabolizing enzymes. Currently under investigation for use in the treatment of PD, safinamide has multiple modes of action including monoamine oxidase B inhibition...
2012: Journal of Experimental Pharmacology
https://www.readbyqxmd.com/read/27132082/dose-dependent-neuroprotective-effect-of-caffeine-on-a-rotenone-induced-rat-model-of-parkinsonism-a-histological-study
#15
Amira M Soliman, Ahmed M Fathalla, Ahmed A Moustafa
Several lines of evidence have demonstrated an inverse relationship between caffeine utilization and Parkinson's disease (PD) progression. Caffeine is a methylxanthine known as a non-specific inhibitor of adenosine (A2A and A1) receptors in the cerebrum and demonstrated to be a neuroprotective medication. In this study, the neuroprotective efficacy of two different doses of caffeine ranging above the usual consumption dose and below the toxic dose was investigated using histopathological and immunohistochemical methods...
June 3, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/26932160/ligand-based-virtual-screening-using-tailored-ensembles-a-prioritization-tool-for-dual-a2aadenosine-receptor-antagonists-monoamine-oxidase-b-inhibitors
#16
REVIEW
Aliuska Morales Helguera, Yunierkis Perez-Castillo, M Natália D S Cordeiro, Eduardo Tejera, César Paz-Y-Miño, Aminael Sánchez-Rodríguez, Marta Teijeira, Evys Ancede-Gallardo, Fernando Cagide, Fernanda Borges, Maykel Cruz-Monteagudo
BACKGROUND: Virtual Screening methodologies have emerged as efficient alternatives for the discovery of new drug candidates. At the same time, ensemble methods are nowadays frequently used to overcome the limitations of employing a single model in ligand-based drug design. However, many applications of ensemble methods to this area do not consider important aspects related to both virtual screening and the modeling process. During the application of ensemble methods to virtual screening the proper validation of the models in virtual screening conditions is often neglected...
2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/26630457/the-efficacy-of-oral-adenosine-a-2a-antagonist-istradefylline-for-the-treatment-of-moderate-to-severe-parkinson-s-disease
#17
Ruxandra Julia Vorovenci, Angelo Antonini
The moderate and severe stages of Parkinson's disease (PD) are marked by motor and non-motor complications that still remain difficult to control with the currently available therapy. Adenosine A(2A) receptor antagonists target non-dopaminergic systems, and have emerged as promising add-on therapy in the management of PD, a little more than a decade ago. While the development of this new drug class was slower than initially expected, istradefylline was recently registered in Japan, because it provides reduction of the off-time, when given in association with levodopa...
2015: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/25746740/the-adenosine-receptor-affinities-and-monoamine-oxidase-b-inhibitory-properties-of-sulfanylphthalimide-analogues
#18
Mietha M Van der Walt, Gisella Terre'Blanche, Anél Petzer, Jacobus P Petzer
Based on a report that sulfanylphthalimides are highly potent monoamine oxidase (MAO) B selective inhibitors, the present study examines the adenosine receptor affinities and MAO-B inhibitory properties of a series of 4- and 5-sulfanylphthalimide analogues. Since adenosine antagonists (A1 and A2A subtypes) and MAO-B inhibitors are considered agents for the therapy of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, dual-target-directed drugs that antagonize adenosine receptors and inhibit MAO-B may have enhanced therapeutic value...
April 2015: Bioorganic Chemistry
https://www.readbyqxmd.com/read/25544641/caffeine-as-a-lead-compound-for-the-design-of-therapeutic-agents-for-the-treatment-of-parkinson-s-disease
#19
REVIEW
Jacobus P Petzer, Anel Petzer
The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain...
2015: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/25175964/clinical-pharmacological-aspect-of-adenosine-a2a-receptor-antagonist-for-dyskinesia
#20
REVIEW
Tomoyuki Kanda, Shin-ichi Uchida
Dopamine replacement therapy using the dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), with a peripheral dopa decarboxylase inhibitor is the most effective treatment currently available for the symptoms of Parkinson's disease (PD). However, the long-term use of dopaminergic therapies for PD is often limited by the development of motor response complications, such as dyskinesia. Adenosine A2A receptors are a promising nondopaminergic target for the treatment of PD. The treatment of motor response complications involves combinations of regular and controlled release L-DOPA, perhaps with the addition of a COMT inhibitor or the use of a longer-acting dopamine agonist...
2014: International Review of Neurobiology
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