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

Abstract

The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A2A adenosine receptors in AD animal and human studies and reports the state of the art of A2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.

Purinergic signaling: A gatekeeper of blood-brain barrier permeation

“…It is a most potent, selective and highly BBB permeable antagonist and is considered to be the first non-nucleotide purine proposition for future drug optimization (Calzaferri et al, 2021). In addition, overexpression (Merighi et al, 2022). Meanwhile, their analysis suggested that alkylxanthines caffeine and DMPX have good ability to cross the blood-brain barrier and are expected to be potential drugs for the treatment of CNS diseases (Merighi et al, 2022).…”

Update on the recent development of allosteric modulators for adenosine receptors and their therapeutic applications

“…Although not yet tested, one can speculate that A 2A AR NAM could potentially counteract in a spatial-selective manner the tumor-increased adenosine immunosuppressive action. In the CNS, blockade of A 2A ARs is indicated, with varying degrees of preclinical and clinical evidence, as a promising therapeutic strategy for Parkinson’s disease, supported by the recent approval of the antagonist istradefylline as add-on therapy ( Chen and Cunha, 2020 ), but also for Alzheimer’s disease ( Merighi et al, 2022 ), acute brain dysfunction ( Cunha, 2016 ), and some neuropsychiatric disorders such as fragile X syndrome, depression, and anxiety ( Domenici et al, 2019 ).…”

The gut microbiota in neurodegenerative diseases: revisiting possible therapeutic targets for cannabidiol

“…A 2A adenosine receptor (A 2A R) is involved in the pathophysiology of different neurodegenerative illnesses. A 2A R modulates glutamatergic synaptic transmission in the CNS, and acts on microglia and astrocyte activation, exerting a pivotal role in neurodegenerative diseases, including AD, particularly regulating neuroinflammation via inhibition of NLRP3 inflammasome (a tripartite multiprotein complex including NLRP3, ASC, and procaspase-1; Merighi et al., 2022a ; for recent reviews see Merighi et al., 2022b , 2022c ). A selective A 2A R antagonist (istradefylline) is already approved in the US and Japan as an adjunctive treatment to levodopa and decarboxylase inhibitors in patients with Parkinson's disease (for a recent review see Mori et al., 2022 ) and this antagonist has been investigated as a putative candidate for the treatment of AD as well; if its effects on AD is confirmed and reproducible, a new hope for AD patients is coming ( Merighi et al., 2022a ; for recent reviews see Merighi et al., 2022b , 2022c ).…”