ADENOSINE RECEPTOR AGONISTS act extra cellularly at receptors variously known as adenosine receptors, P1 purine receptors, P1 receptors, P1 purinoceptors, or nucleoside receptors. Adenosine receptors have a wide range of mainly inhibitory actions in the body, including cardiac slowing, a fall in blood pressure, dilation of bloqd vessels, inhibition of platelet aggregation, inhibition of intestinal movements and actions within the central nervous system.

Subtypes of adenosine receptors exist — A1, A2 and A3 — which have differential sensitivities to adenosine nucleoside analogues, including 2-methylthio-AMP, 2-thioadenosine, DPMA, IB-MECA, NECA, CPA, CCPA and DPCPX. These receptors, and subtypes within A2, have all been cloned. They have structures typical of the seven-transmembrane G-protein-coupled superfamily of receptors, but have amongst the shortest sequences known (A3 has only 318 amino acids), and a lack of sequence similarity with any other receptors appears to put them in a class of their own. Adenosine receptors are not sensitive to nucleotides such as ADP (adenosine diphosphate) and ATP (adenosine triphosphate), which instead act as P2 receptor agonists that are nucleotide-preferring (see P2 receptor agonists)

A1 receptors are selectively activated by CPA, CCPA and GR 79236. Coupling is negatively to adenylyl cyclase (Gi/o). They have been cloned from human and other sources, and show a wide distribution in the body. There is pharmaceutical interest in this receptor in view of the beneficial actions that adenosine and its analogues can have on the heart, including a block of conduction that may mean it can be antiarrhythmic. A, receptors reduce neurotransmitter release from neurons in the peripheral and central nervous systems, and the overall effects on the CNS is depression, reduced anxiety, sleep and a neuroprotective action (possibly through reduced glutamate release when this is induced by trauma, ischaemia etc.). The actions of xanthines, such as caffeine, which are antagonists at adenosine receptors, have largely the opposite actions. See ADENOSINE RECEPTOR ANTAGONISTS.

A2 receptors have been divided into subtypes. At A2A receptors CGS 21680 has a high affinity. A2B receptors are similar, but have lower affinity for the agonists. A2 receptors inhibit platelet aggregation, may stimulate nociceptive afferents, and cause vasodilatation (including in the coronary circulation). There are high concentrations of A2 receptors in certain areas of the brain, suggesting an interaction with dopaminergic systems. A2A receptors on polymorphonuclear leucocytes reportedly delay apoptosis and may have a normal brake’ role. A2B receptors are thought to be involved in degranulation of mastocytoma cells and certain mast cells in the lung, suggesting asthma and allergic lung disease as possible therapeutic targets.

A3 receptors are selectively activated by the adenosine analogues IB-MECA and 2-chloro-IB-MECA, which show higher affinity compared to A, receptors. A3 receptors show a 58% identity with cloned A1 and A2 receptors. Coupling is negatively to adenylyl cyclase (Gi/o). Analysis of mRNA expression show highest levels in the testes, low levels in the lung, kidneys, heart and some parts of the CNS. The high-expression level of the A3 receptor in the testes suggests a possible role for adenosine in reproduction. This receptor subtype has been shown functionally to be expressed on white blood cells such as mast cells. There is recent evidence that activation of A3 receptors on macrophages reduces endotoxin-evoked cytokine release, antigen-evoked responses in a mast cell line, and that there was reduced apoptosis in lymphocytes and astrocytes. These models of infection and disease suggest possible therapeutic uses of adenosine A3 receptor agonists.

Adenosine can be used therapeutically, by intravenous injection, as an antiarrhythmic, when it rapidly corrects certain abnormal cardiac rhythms, and also aids in diagnosis of certain arrhythmias. Dipyridamole acts as though it stimulates adenosine receptors, but does so indirectly by virtue of inhibiting adenosine uptake, thus prolonging the action of endogenous adenosine. It can therefore be used therapeutically as an antiplatelet drug to prevent thrombosis, though it is not an anticoagulant. See ANTIARRHYTHMICS; PLATELET AGGREGATION INHIBITING AGENTS.