A_2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders

Abstract

11: Endogenous nucleoside adenosine modulates a number of physiological effects through interaction with P1 purinergic receptors. All of them are G protein coupled receptors and, to date, four subtypes have been characterized and named A1, A2A, A2B, and A3. In recent years adenosine receptors, particularly the A2A subtype, have become attractive targets for the treatment of several neurodegenerative disorders, known to involve neuroinflammation, like Parkinson’s and Alzheimer’s diseases, multiple sclerosis and neuropsychiatric conditions. In fact, it has been demonstrated that inhibition of A2A adenosine receptors exerts neuroprotective effects counteracting neuroinflammatory processes and astroglial and microglial activation. The A2A adenosine receptor antagonist istradefylline, developed by Kyowa Hakko Kirin Inc., was approved in Japan as adjunctive therapy for the treatment of Parkinson’s disease and very recently it was approved also by the US Food and Drug Administration. These findings pave the way for new therapeutic opportunities, so, in this review, a summary of the most relevant and promising A2A adenosine receptor antagonists will be presented along with their preclinical and clinical studies in neuroinflammation related diseases.

“Dual Anta-Inhibitors” of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

“…Another target that seems to play a crucial role in neuroinflammatory processes, neurodegenerative disorders, and cancer is the adenosine A 2A receptor (A 2A AR), activated by the naturally occurring nucleoside adenosine (Ado) [ 12 , 13 , 14 ]. ARs belong to the superfamily of G protein coupled receptors (GPCRs) and, to date, four subtypes named A 1 , A 2A , A 2B , and A 3 have been cloned and characterized.…”

Dual Anta-Inhibitors Targeting Protein Kinase CK1δ and A2A Adenosine Receptor Useful in Neurodegenerative Disorders

“…Recent evidence shows the involvement of the A 2A adenosine receptor (A 2A AR) in the neuroinflammation that accompanies neurodegenerative diseases [ 20 , 21 , 22 , 23 , 24 ]. A 2A AR is highly expressed in microglial cells, a type of glial cell that is responsible for the first and main active immune defense in the central nervous system (CNS) [ 25 ].…”

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

“…In fact, it reversed the catalepsy induced by haloperidol and induced contralateral turning behavior in rats sensitized to L-DOPA. Moreover, this compound showed good efficacy in lowering the intensity of the tremor evoked by Parkinson's induced by tacrine and in reducing the motor deficit in a neuronal injury model induced by 6-hydroxydopamine [30]. Despite these promising results, ANR 94 does not show a remarkable affinity for A 2A ARs (Ki = 46 nM) with respect to other A 2A AR antagonists like as ZM241385, which is considered the reference compound for studying the A 2A AR.…”