Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

Abstract

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

Adenosine Receptor Agonists Increase the Inhibition of Platelet Function by P2Y12 Antagonists in a cAMP- and Calcium-Dependent Manner

“…Such the approach was chosen deliberately since it is known that endogenous adenosine undergoes rapid and excessive uptake and metabolism by erythrocytes [ 42 ]. Synthetic AR agonists investigated in this work were reported [ 13 , 20 , 43 ] to be much more stable in blood, we decided to use the experimental conditions mimicking the physiological ones, and also our aim was to minimize a risk of the incidental platelet activation during the process of the isolation of platelet-rich plasma or platelets.…”

“…Among synthetic AR agonists, most do not differentiate between A 2A or A 2B subtypes, but some selective agonists have been identified. AR agonists are believed to block platelet aggregation [ 15 , 16 , 17 ], and hence interest in their antiplatelet property has been growing [ 13 , 18 , 19 , 20 ].…”

Adenosine Signaling in Mast Cells and Allergic Diseases

“…Adenosine is a nucleoside that produces both pro-inflammatory and anti-inflammatory effects depending on the model used. Adenosine acts through the binding to specific receptors that are widely distributed throughout the human body [ 7 , 68 ]. In fact, adenosine produces opposite effects depending on its concentration, cell type, organ and species [ 48 ].…”

ATP and Adenosine in the Retina and Retinal Diseases

“…Adenosine possesses anti-inflammatory properties in retina ( Aires et al, 2019a ; Aires et al, 2019b ). The increased adenosine at inflamed sites can protect against cellular damage by activating A2AR ( Ibrahim et al, 2011 ), by inhibiting release of TNF-α from microglia induced by hypoxia and lipopolysaccharide, and by inhibiting microgliosis ( Jamwal et al, 2019 ). Cannabidiol, an anti-inflammatory molecule, prevents the adenosine uptake and subsequently activates adenosine A2AR to inhibit retinal microglia activation ( Liou et al, 2008 ).…”