Adenosine A2A Receptor as a Potential Drug Target - Current Status and Future Perspectives

Abstract

Adenosine receptors (ARs) are a class of G-protein coupled receptors (GPCRs) that are activated by the endogenous substance adenosine. ARs are classified into 4 subtype receptors, namely, the A1, A2A, A2B and A3 receptors. The wide distribution and expression of the ARs in various body tissues as well as the roles they have in controlling different functions in the body make them potential drug targets for the treatment of various pathological conditions, such as cardiac diseases, cancer, Parkinson’s disease, inflammation and glaucoma. Therefore, in the past decades, there have been extensive investigations of ARs with a high number of agonists and antagonists identified that can interact with these receptors. This review shall discuss the A2A receptor (A2AAR) subtype of the ARs. The structure, properties and the recent advances in the therapeutic potential of the receptor are discussed with an overview of the recent advances in the methods of studying the receptor. Also, molecular modeling approaches utilized in the design of A2AAR ligands are highlighted with various recent examples.

Piperazine- and Piperidine-Containing Thiazolo[5,4-d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists

“…Most of the tested compounds (2-3, 6-8, 10-15, 19-20) displayed high to good affinity for the hA 2A AR (8.62 nM < K i < 187 nM). Instead, no significant affinity was detected for the off-target hARs with the exception of that of compounds 3-5, 11, 20 which bind the hA 1 (3,11,20) and the hA 3 subtypes (4-5) with good affinities.…”

“…The A 2A AR is located both peripherally and centrally, with the highest expression levels in the striatum, olfactory tubercle, and the immune system. The A 2A AR is a very promising target in the field of neurodegenerative pathologies, mainly Parkinson’s (PD) and Alzheimer’s (AD) diseases [ 3 , 4 , 5 ]. Several A 2A AR antagonists have demonstrated to improve PD motor dysfunctions in various preclinical animal models as well as in clinical studies [ 5 ].…”

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

“…Reductions to A 1 R and A 2A R protein expression Neural Plasticity could contribute to reduced efficacy of adenosine-mediated inhibition of dopamine activity in the striatum, which should be followed up in more detail by future studies. Indeed, changes in A 1 Rs and A 2A Rs that are dependent on physical activity status could affect therapeutic approaches for psychiatric and neurological diseases that involve abnormal dopamine signaling in the striatum, including addiction, depression, Parkinson's disease, and Huntington's disease, among many others [94][95][96][97][98][99][100][101][102][103][104]. Therefore, the current findings could be of importance for understanding the mechanisms contributing to exercise-improved cognitive function, as well as the prevention and treatment of mental health and neurobiological disorders that involve the striatum.…”

Adenosine A_2A Receptor Agonist PSB-0777 Modulates Synaptic Proteins and AMPA Receptor Expression in a Dose- and Time-Dependent Manner in Rat Primary Cortical Neurons

“…Time-and Dose-Dependent Regulation of Vglut1-Positive Glutamatergic Synapses by PSB-0777 Previous studies have illuminated a crucial role of excitatory glutamate synapses in synaptic plasticity and synaptic transmission. 46) Altered glutamate signalling is related to some psychiatric disorders, 47) and the A 2A receptor acts as a neuroregulator that can mediate the glutamatergic signalling pathway. 24) Thus, we continued to explore the formation of glutamatergic synapses by double immunofluorescence staining with anti-Vglut1 (an excitatory glutamatergic neuronal marker)/anti-PSD95 antibodies after treatment with PSB-0777 for 30 min, 24 h, or 3 d. Quantitative analysis of colocalized puncta of Vglut1/ PSD95 revealed an elevation of Vglut1-positive glutamatergic synapses in a time-and dose-dependent manner.…”

“…Disrupted glutamatergic synapse function has been found in ASD and SCZ. 42,47,57,75) Glutamate is the major excitatory transmitter. To maintain synaptic efficacy, recycled SVs are refilled with glutamate by Vgluts.…”