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Adenosine A(2A) Receptor Antagonists and Parkinson's Disease.

ABSTRACT: This Review summarizes and updates the work on adenosine A(2A) receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson's disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A(2A) antagonists, but a few approaches to dual A(2A)/A(1) antagonists will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials.

SUBMITTER: Shook BC

PROVIDER: S-EPMC3369712 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Adenosine A(2A) Receptor Antagonists and Parkinson's Disease.

Shook Brian C BC Jackson Paul F PF

ACS chemical neuroscience 20110621 10

This Review summarizes and updates the work on adenosine A(2A) receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson's disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and oth ...[more]

PMID: 22860156

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Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease.

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| S-EPMC6178748 | biostudies-literature

Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease.

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| S-EPMC3205226 | biostudies-literature

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Identification of novel adenosine A(2A) receptor antagonists by virtual screening.

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| S-EPMC3308209 | biostudies-literature

Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer's Disease.

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| S-EPMC9102440 | biostudies-literature

Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists.

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| S-EPMC2826142 | biostudies-literature

A2A Adenosine Receptor Antagonists: Are Triazolotriazine and Purine Scaffolds Interchangeable?

Project description:The A2A adenosine receptor (A2AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A2AAR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A2AAR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.

| S-EPMC9032385 | biostudies-literature

Adenosine A2A receptor antagonists: from caffeine to selective non-xanthines.

Project description:A long evolution of knowledge of the psychostimulant caffeine led in the 1960s to another purine natural product, adenosine and its A2A receptor. Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four different adenosine receptors in a manner opposite to the pan-antagonist caffeine and serves as an endogenous allostatic regulator. Although detrimental in the developing brain, caffeine appears to be cerebroprotective in aging. Moderate caffeine consumption in adults, except in pregnancy, may also provide benefit in pain, diabetes, and kidney and liver disorders. Inhibition of A2A receptors is one of caffeine's principal effects and we now understand this interaction at the atomic level. The A2A receptor has become a prototypical example of utilizing high-resolution structures of GPCRs for the rational design of chemically diverse drug molecules. The previous focus on discovery of selective A2A receptor antagonists for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

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Adenosine A2A receptor availability in patients with early- and moderate-stage Parkinson's disease.

Project description:IntroductionAdenosine 2A (A2A) receptors co-localize with dopamine D2 receptors in striatopallidal medium spiny neurons of the indirect pathway. A2A receptor activation in the striatum or pallidum decreases D2 signaling. In contrast, A2A receptor antagonism may help potentiate it. Furthermore, previous PET studies have shown increased A2A receptor availability in striatum of late-stage PD patients with dyskinesia. However, human in vivo evidence for striatal A2A receptor availability in early-stage PD is limited. This study aimed to investigate possible differences in A2A receptor availability in the striatum and pallidum of early- and moderate-stage PD patients without dyskinesias.MethodsBrain MRI and PET with [11C]TMSX radioligand, targeting A2A receptors, was performed in 9 patients with early- and 9 with moderate-stage PD without dyskinesia and in 6 healthy controls. Distribution volume ratios (DVR) were calculated to assess specific [11C]TMSX binding in caudate, putamen and pallidum.ResultsA2A receptor availability (DVR) was decreased in the bilateral caudate of early-stage PD patients when compared with healthy controls (P = 0.02). Conversely, DVR was increased bilaterally in the pallidum of moderate-stage PD patients compared to healthy controls (P = 0.03). Increased mean striatal DVR correlated with higher motor symptom severity ([Formula: see text] = 0.47, P = 0.02).ConclusionOur results imply regional and disease stage-dependent changes in A2A receptor signaling in PD pathophysiology and in response to dopaminergic medication.

| S-EPMC9813038 | biostudies-literature

Adenosine A(2A) Receptor Binding Profile of Two Antagonists, ST1535 and KW6002: Consideration on the Presence of Atypical Adenosine A(2A) Binding Sites.

Project description:Adenosine A(2A) receptors seem to exist in typical (more in striatum) and atypical (more in hippocampus and cortex) subtypes. In the present study, we investigated the affinity of two adenosine A(2A) receptor antagonists, ST1535 [2 butyl -9-methyl-8-(2H-1,2,3-triazol 2-yl)-9H-purin-6-xylamine] and KW6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6,dione] to the "typical" and "atypical" A(2A) binding sites. Affinity was determined by radioligand competition experiments in membranes from rat striatum and hippocampus. Displacement of the adenosine analog [(3)H]CGS21680 [2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarbox-amidoadenosine] was evaluated in the absence or in the presence of either CSC [8-(3-chlorostyryl)-caffeine], an adenosine A(2A) antagonist that pharmacologically isolates atypical binding sites, or DPCPX (8-cyclopentyl-1,3-dipropylxanthine), an adenosine A(1) receptor antagonist that pharmacologically isolates typical binding site. ZM241385 [84-(2-[7-amino-2-(2-furyl) [1,2,4]-triazol[2,3-a][1,3,5]triazin-5-yl amino]ethyl) phenol)] and SCH58261 [(5-amino-7-(?-phenylethyl)-2-(8-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c) pyrimidine], two other adenosine A(2A) receptor antagonists, which were reported to differently bind to atypical and typical A(2A) receptors, were used as reference compounds. ST1535, KW6002, ZM241385 and SCH58261 displaced [(3)H]CGS21680 with higher affinity in striatum than in hippocampus. In hippocampus, no typical adenosine A(2A) binding was detected, and ST1535 was the only compound that occupied atypical A(2A) adenosine receptors. Present data are explained in terms of heteromeric association among adenosine A(2A), A(2B) and A(1) receptors, rather than with the presence of atypical A(2A) receptor subtype.

| S-EPMC3059644 | biostudies-literature

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