Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines

Neustadt, Bernard R.; Liu, Hong; Hao, Jinsong; Greenlee, William J.; Stamford, Andrew W.; Foster, Carolyn; Arik, Leyla; Lachowicz, Jean E.; Zhang, Hongtao; Bertorelli, Rosalia; Fredduzzi, Silva; Varty, Geoffrey B.; Cohen-Williams, Mary; Ng, Kwokei

doi:10.1016/j.bmcl.2008.11.075

Cited by 36 publications

(29 citation statements)

References 21 publications

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“…Preladenant has over 1000-fold selectivity for A2A receptors compared to the other adenosine receptors in in vitro expression systems and has been studied in models of PD where it reduces motor impairments and depression-like behavior and affects microglial motility in brain slices (Hodgson et al, 2009; Hodgson et al, 2010; Gyoneva et al, 2014b; Neustadt et al, 2007). …”

Section: Methodsmentioning

confidence: 99%

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

et al. 2016

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Alzheimer’s disease (AD), the most common form of dementia in the elderly, is characterized by the presence of extracellular plaques composed of amyloid β (Aβ) peptides and intracellular tau aggregates. The plaques are surrounded by microglia, the brain’s resident immune cells, which likely participate in the clearance of Aβ by phagocytosis. The microglia that are associated with plaques display an abnormal amoeboid morphology and do not respond to tissue damage, in contrast to microglia in healthy brains. Here, we used time lapse confocal microscopy to perform a detailed real time examination of microglial motility in acute hippocampal brain slices from the 5xFAD mouse model of AD, which was crossed to Cx3cr1GFP/GFP mice to achieve microglia-specific GFP expression for visualization. During baseline conditions, microglia around plaques appeared hypermotile, moving the processes that were pointing away from plaques at higher speed than microglia not associated with plaques. Yet, neither plaque-associated, nor plaque-free microglia were able to extend processes towards sites of modest mechanical damage. Application of the selective adenosine A2A receptor antagonist preladenant, which restores microglial response to cellular damage in a mouse model of Parkinson’s disease, reduced the hypermotility of plaque-associated microglia, but did not restore motility towards damaged cells in slices from 5xFAD mice. Our results suggest that process hypermotility and resistance to A2A antagonism during response to tissue damage may represent unique functional phenotypes of plaque-associated microglia that impair their ability to function properly in the AD brain.

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Section: Methodsmentioning

confidence: 99%

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

et al. 2016

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“…132 Schering-Plough has described several attempts to replace the 2-furanyl ring of SCH58261 analogs with other aryl groups, more stable from a metabolic point of view. 127,133 Nevertheless 2-phenyl/heteroaryl derivatives have been found to be generally less potent and/or selective. We have found a similar result in the pyrrolo [3,2- Fig.…”

Section: A Pyrazolo[43-e][124]triazolo[15-c]pyrimidines (Ptps)mentioning

confidence: 99%

“…The compound showed an acceptable in vitro profile combined with elevated plasma levels after oral administration and protracted in vivo activity in a rat haloperidol-induced catalepsy model. 133 Compound 65 is representative of a very recent series of triazolopyrimidines exerting AR antagonist activity with a different selectivity profile (mainly A 2A or A 3 ) in relation to the kind of substitutions at the 5-and 8positions. 189 A free 5-amino group combined with the 8-ethoxycarbonyl function led to good hA 2A binding affinity (K i hA 2A AR = 3.32 nM) and reasonable selectivity over the other ARs (see Table II).…”

Section: F Triazolo-triazines/pyrimidinesmentioning

confidence: 99%

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Preti

Baraldi

Moorman³

et al. 2015

Med. Res. Rev.

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Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.

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“…This assay involves antagonizing D 2 receptors in medium striatal spiny neurons of the indirect pathway and it has been used to assess the potential symptomatic efficacy of novel non-dopaminergic agents in PD, including mGlu 4 -positive allosteric modulators, adenosine A 2A /A 1 antagonists and mGlu 7 agonists (Greco et al, 2010;Neustadt et al, 2009;Niswender et al, 2008;Shook et al, 2010). The blockade of D 2 receptors by haloperidol (1 mg/kg) results in rigidity and catalepsy in rodents that mimics a key symptom of PD, namely the difficulty of patients to initiate movement.…”

Section: Urb597 Relieves Pd Symptoms Via Cb 1 and Cb 2 Receptorsmentioning

confidence: 99%

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

Celorrio

Fernández-Suárez

Rojo-Bustamante

et al. 2016

Brain, Behavior, and Immunity

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Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5weeks. URB597 (1mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.

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Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines

Cited by 36 publications

References 21 publications

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

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Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines

Cited by 36 publications

References 21 publications

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

Altered motility of plaque-associated microglia in a model of Alzheimer’s disease

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease

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Product

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History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents