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Adenosine receptors as therapeutic targets

Key Points

  • Modulation of adenosine receptors (ARs) using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders.

  • Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and adenosine.

  • The A1, A2A, A2B and A3 are the four known subtypes of adenosine receptors (ARs). All four subtypes are members of the superfamily of G-protein-coupled receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling.

  • Classically, AR signalling is thought to occur through inhibition or stimulation of adenylyl cyclase (also known as adenylate cyclase). However, it is now apparent that other pathways, such as phospholipase C, Ca2+ and mitogen-activated protein kinases, are also relevant.

  • Modification of adenosine has been the key strategy for discovering AR agonists and the structure–activity relationships of adenosine at ARs have been extensively probed. Highly selective agonists of the different ARs have been designed through both empirical approaches and a semi-rational approach based on molecular modelling.

Abstract

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

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Figure 1: Adenosine receptor signalling pathways.
Figure 2: Adenosine receptor agonists.
Figure 3: Adenosine receptor agonists.
Figure 4: Adenosine receptor antagonists.
Figure 5: Adenosine receptor antagonists.
Figure 6: Examples of allosteric enhancers of the activity of adenosine receptor agonists.
Figure 7: Novel disease targets for selective adenosine receptor ligands.

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Glossary

Angiogenesis

The growth of new blood vessels — for example, in pathology, the generation of a blood supply to a tumour.

Allosteric site

A modulatory binding site on a receptor that is topographically distinct from the agonist binding site.

Pertussis toxin

A compound that inhibits the guanine nucleotide binding proteins Gi and Go via ADP-ribosylation.

Bradycardiac effect

An arrhythmia typified by an abnormally slow heart rate.

Mast cell

A type of leukocyte that has large secretory granules that contain histamine and various protein mediators.

Photoisomerization

A conversion between structural isomers caused by light-induced excitation.

Paroxysmal supraventricular tachycardia

(PSVT). A regular, abnormally fast heart beat caused by rapid firing of electrical impulses from a focus above the AV (atrioventricular) node.

Atrial fibrillation

A condition in which disorganized electrical conduction in the atrial walls results in ineffective pumping of blood into the ventricle and an irregular heart rhythm.

Dromotropic

Refers to velocity of AV nodal conduction in the heart.

Discriminative stimulus

In instrumental conditioning, the external stimulus that signals a particular relationship between the instrumental response and the reinforcer.

Somnogenic

Sleep-inducing.

TH2 cytokines

Cytokines such as interleukin (IL)-3, -4, -5, -6, -10 and -12 secreted by TH2 helper T lymphocytes to control various aspects of the antibody response.

Bioavailability

The fraction or percentage of an administered drug or other substance that becomes available to the target tissue after administration.

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Jacobson, K., Gao, ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov 5, 247–264 (2006). https://doi.org/10.1038/nrd1983

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