It has been established for several decades that extracellular adenosine is an important modulator of physiological and pathological processes that can be safely targeted by adenosine receptor agonists or antagonists. Experimental studies have clarified the biological functions of four adenosine receptors, which represent pharmacological targets for the treatment of several human diseases including neurological, inflammatory or ischaemic conditions.
Despite several years of efforts, including several large Phase III clinical trials of adenosine receptor drugs, very few agents have actually made it to the clinic owing to insufficient efficacy and/or unacceptable side effects.
Based on this discrepancy, we discuss the therapeutic potential of adenosine receptor modulators, focusing on the key biological factors limiting their clinical development and the hurdles that could and should be overcome.
A major challenge in developing adenosine receptor ligands for specific clinical applications is that adenosine has so many roles. Thus, demonstrating the effects of drugs causing adenosine receptor activation or inactivation on specific systems under distinct experimental settings is not sufficient to prove that they can be delivered in a manner that is clinically effective and safe for treating human disease.
We discuss the complexity of adenosine signalling and drug effects over the continuum of specific disease courses, addressing the implications for the use of adenosine receptor-targeting agents.
The adenosine receptor antagonist caffeine, which is commonly ingested, complicates the interpretation of clinical trials, and a careful assessment of the caffeine intake of individual patients is vital in assessing a patient's response to adenosine receptor-targeting drugs.
Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.
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The authors thank E. Augusto and M. Marco for help with the figure. This research was supported by: a grant from the US National Institutes of Health (NIH/NS 041083–07) and the Cogan Foundation, and grants from the Jerry McDonald Huntington's Disease Research Fund to J.C.; grants from the US National Institutes of Health (NIH), the US National Heart, Lung, and Blood Institute (NHLBI) and the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01-HL0921, R01-DK083385 and R01-HL098294) and a grant from the Crohn's & Colitis Foundation of America (CCFA) to H.K.E.; and a grant from the Swedish Science Research Council (grant no. 2553) to B.B.F.
The authors declare no competing financial interests.
Purine derivatives with a common xanthine core molecule and methyl group attached in various combinations to nitrogens. The most common methylxanthines include caffeine, theophylline, theobromine and paraxanthine.
- G protein-coupled receptor
(GPCR). A cell membrane protein characterized by a seven-transmembrane structure, which is coupled to trimeric G proteins; GPCRs elicit diverse sets of signalling and biological functions.
- Ectonucleoside triphosphate diphosphohydrolase 1
(ENTPD1; also known as CD39). A membrane-bound enzyme with enzymatic activity in the extracellular space; ENTPD1 catalyses the conversion of extracellular ATP and/or ADP to AMP — an important step in generating extracellular adenosine.
(NT5E; also known as CD73). A membrane-bound enzyme with enzymatic activity in the extracellular space; NT5E catalyses the conversion of extracellular AMP to adenosine, thereby functioning as a pacemaker enzyme for generating extracellular ATP-derived adenosine.
- Acute heart failure
A gradual or rapid change in the signs and symptoms of heart failure. Many pathological factors, including worsening renal function, persistent neurohormonal activation and progressive deterioration in myocardial function, all contribute to the development of acute heart failure.
- Parkinson's disease
A neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the accumulation of proteinaceous intracellular inclusions (Lewy bodies), leading to decreased dopamine levels in the striatum and cardinal motor symptoms.
- Ischaemic preconditioning
A phenomenon in which repeated short periods of exposure to sublethal ischaemia induce tolerance and protection against subsequent lethal ischaemic injury.
- Adenosine kinase
An enzyme that converts intracellular adenosine to AMP, which is critically important in setting the basal adenosine level. Hypoxia is associated with transcriptional repression of adenosine kinase, thereby resulting in increased intracellular adenosine levels and enhanced extracellular adenosine signalling.
- Hypoxia-inducible factor
(HIF). Key transcription factor for hypoxia-induced responses that are critical in adapting hypoxic or ischaemic tissues to conditions of limited oxygen availability.
- Bleomycin-induced lung injury
A widely used antitumour agent causing single- and double-stranded breaks in cellular DNA, leading to genomic instability of damaged cells. Bleomycin induces apoptosis and increases the production of reactive oxygen species, resulting in oxidative stress and pulmonary fibrosis.
- Adenosine deaminase
An enzyme that converts adenosine to inosine (and deoxyadenosine to deoxyinosine). Lack of adenosine deaminase causes immune deficiency.
G protein-coupled receptors (GPCRs) can exist in a monomeric state or form dimeric, multimeric or oligomeric structures. Hetero-oligomerization of GPCRs, involving several gene products, can potentially lead to an altered biological response repertoire.
- Allosteric enhancers
Allosteric modulators do not have any activity by themselves, but as they bind to the allosteric site (which is distinct from the primary ligand binding orthosteric site) they can alter the receptor confirmation by an orthosteric ligand in such a way that the response to it is increased.
- Equilibrative nucleoside transporter 1
(ENT1). A channel located in the cell membrane; along with ENT2, ENT1 speeds up the bi-directional transport of adenosine across the cell membrane along its gradient.
- Functional selectivity
Also known as biased signalling; an emerging concept of G protein-coupled receptor (GPCR) function. For example, some GPCR ligands preferentially activate signals via β-arrestins, others via G proteins.
An adaptor protein that was initially recognized as a negative regulator of G protein signalling but is now recognized to be a multifunctional adaptor that can not only mediate G protein-coupled receptor (GPCR) internalization and desensitization but also produce distinct intracellular signalling and hence functional consequences.
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Chen, JF., Eltzschig, H. & Fredholm, B. Adenosine receptors as drug targets — what are the challenges?. Nat Rev Drug Discov 12, 265–286 (2013). https://doi.org/10.1038/nrd3955
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