Read by QxMD icon Read

Adenosine receptor inhibitor in Parkinson's disease

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
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
Maykel Cruz-Monteagudo, Fernanda Borges, M Natália D S Cordeiroc, Aliuska Morales Helguerad, Eduardo Tejerab, Cesar Paz-Y-Miñob, Aminael Sánchez-Rodrígueze, Yunier Perera-Sardiñaf, 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...
January 16, 2017: Current Neuropharmacology
Yunierkis Perez-Castillo, Aliuska Morales Helguera, M Natália D S Cordeiro, Eduardo Tejera, Cesar Paz-Y-Miño, Aminael Sánchez-Rodríguez, Fernanda Borges, Maykel Cruz-Monteagudo
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. To the best of our knowledge, no theoretical study has been devoted to developing structure-based virtual screening methodologies for the discovery of dual A2AAR antagonists and MAO-B inhibitors...
January 9, 2017: Current Neuropharmacology
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 6, 2017: Molecular Neurobiology
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
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
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
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
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
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
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
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
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
Dalila Mango, Alessandra Bonito-Oliva, Ada Ledonne, Loredana Cappellacci, Riccardo Petrelli, Robert Nisticò, Nicola Berretta, Gilberto Fisone, Nicola Biagio Mercuri
γ-Aminobutyric acid A receptor (GABAAR)-mediated postsynaptic currents were recorded in brain slices from substantia nigra pars reticulate neurons. The selective adenosine A1 receptor (A1R) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), increased the frequency, but not the amplitude of spontaneous inhibitory post-synaptic currents (IPSCs) in the presence of the dopamine D1 receptor agonist SKF 38393 (SKF) and phosphodiesterase 10A inhibitors (papaverine or AE90074). Under these conditions, DPCPX also increased the amplitude of evoked IPSCs (eIPSCs)...
November 2014: Experimental Neurology
Deepak Mittal, Arabella Young, Kimberley Stannard, Michelle Yong, Michele W L Teng, Bertrand Allard, John Stagg, Mark J Smyth
Adenosine targeting is an attractive new approach to cancer treatment, but no clinical study has yet examined adenosine inhibition in oncology despite the safe clinical profile of adenosine A2A receptor inhibitors (A2ARi) in Parkinson disease. Metastasis is the main cause of cancer-related deaths worldwide, and therefore we have studied experimental and spontaneous mouse models of melanoma and breast cancer metastasis to demonstrate the efficacy and mechanism of a combination of A2ARi in combination with anti-PD-1 monoclonal antibody (mAb)...
July 15, 2014: Cancer Research
F I Tarazi, Z T Sahli, M Wolny, S A Mousa
The prevalence of Parkinson's disease (PD) increases with age and is projected to increase in parallel to the rising average age of the population. The disease can have significant health-related, social, and financial implications not only for the patient and the caregiver, but for the health care system as well. While the neuropathology of this neurodegenerative disorder is fairly well understood, its etiology remains a mystery, making it difficult to target therapy. The currently available drugs for treatment provide only symptomatic relief and do not control or prevent disease progression, and as a result patient compliance and satisfaction are low...
November 2014: Pharmacology & Therapeutics
João Ananias Machado-Filho, Alyne Oliveira Correia, Anyssa Brilhante Aires Montenegro, Maria Elizabeth Pereira Nobre, Gilberto Santos Cerqueira, Kelly Rose Tavares Neves, Maria da Graça Naffah-Mazzacoratti, Esper Abrão Cavalheiro, Gerly Anne de Castro Brito, Glauce Socorro de Barros Viana
Several lines of evidences have shown the inversion association between coffee consumption and Parkinson's disease (PD) development. Caffeine is a methylxanthine known as a non-selective inhibitor of A2A and A1 adenosine receptors in the brain and shown to be a neuroprotective drug. The objectives were to study caffeine effects in a unilateral 6-OHDA model of PD in rats. Male rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned and 6-OHDA-lesioned and treated for 2 weeks with caffeine (10 and 20mg/kg, p...
May 1, 2014: Behavioural Brain Research
Koji Yamada, Minoru Kobayashi, Shizuo Shiozaki, Teruko Ohta, Akihisa Mori, Peter Jenner, Tomoyuki Kanda
RATIONALE: Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. OBJECTIVE: We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. RESULTS: Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine...
July 2014: Psychopharmacology
Annalisa Pinna, Jordi Bonaventura, Daniel Farré, Marta Sánchez, Nicola Simola, Josefa Mallol, Carme Lluís, Giulia Costa, Younis Baqi, Christa E Müller, Antoni Cortés, Peter McCormick, Enric I Canela, Eva Martínez-Pinilla, José L Lanciego, Vicent Casadó, Marie-Therese Armentero, Rafael Franco
Long-term therapy with L-3,4-dihydroxyphenylalanine (L-DOPA), still the most effective treatment in Parkinson's disease (PD), is associated with severe motor complications such as dyskinesia. Experimental and clinical data have indicated that adenosine A2A receptor antagonists can provide symptomatic improvement by potentiating L-DOPA efficacy and minimizing its side effects. It is known that the G-protein-coupled adenosine A2A, cannabinoid CB1 and dopamine D2 receptors may interact and form functional A2A-CB1-D2 receptor heteromers in co-transfected cells as well as in rat striatum...
March 2014: Experimental Neurology
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"