Elsevier

Biochemical Pharmacology

Volume 151, May 2018, Pages 157-165
Biochemical Pharmacology

Review
The therapeutic potential of purinergic signalling

https://doi.org/10.1016/j.bcp.2017.07.016Get rights and content

Abstract

This review is focused on the pathophysiology and therapeutic potential of purinergic signalling. A wide range of diseases are considered, including those of the central nervous system, skin, kidney, musculoskeletal, liver gut, lower urinary tract, cardiovascular, airways and reproductive systems, the special senses, infection, diabetes and obesity. Several purinergic drugs are already on the market, including P2Y12 receptor antagonists for stroke and thrombosis, P2Y2 receptor agonists for dry eye, and A1 receptor agonists for supraventricular tachycardia. Clinical trials are underway for the use of P2X3 receptor antagonists for the treatment of chronic cough, visceral pain and hypertension, and many more compounds are being explored for the treatment of other diseases. Most experiments are ‘proof of concept’ studies on animal or cellular models, which hopefully will lead to further clinical trials. The review summarises the topic, mostly referring to recent review articles.

Introduction

Mike Williams was a pioneer for considering the therapeutic potential of purinergic signalling and he may be surprised to learn about the massive current developments by scientists, clinicians and drug companies on this topic. I will give an overview of these developments in this article.

The receptor subtypes for purines and pyrimidines are diverse, currently consisting of 4 subtypes of the P1 (adenosine) receptor (A1, A2A, A2B and A3), 7 subtypes of P2X ion channel receptors (P2X1-P2X7) and 8 subtypes of P2Y G protein-coupled receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14) (see [1]) and they are expressed on nearly all cell types (see [2] for detailed coverage of the expression and roles of P2 receptors, and [3] as well as the Special Issue published in Neuropharmacology (Volume 104, Pages 1–282, 2016) which contains considerable coverage of the therapeutic roles of P1 receptors).

Several purinergic compounds are already on the market, including clopidogrel and ticagrelor, widely used P2Y12 receptor antagonists of platelet aggregation for the treatment of thrombosis and stroke (see [4] and Fig. 1a); a long acting P2Y2 receptor agonist for the treatment of dry eye; and A1 receptor agonists for the treatment of supraventricular tachycardia. There are currently clinical trials taking place with P2X3 antagonists that are orally bioavailable and stable in vivo for the treatment of chronic cough, visceral pain (see Fig. 1b), bladder diseases and hypertension. I will now summarise, mostly with recent review articles, the studies done on diseases of nearly all the bodily systems (see reviews [5], [6], [7]).

Section snippets

Diseases of the central nervous system

P2X7 receptor antagonists are promising targets for the treatment of neurodegenerative diseases (see [8], [9]), including Brilliant Blue G (BBG) for Alzheimer’s [10] and Parkinson’s [11] diseases, multiple sclerosis [12], amyotrophic lateral sclerosis [13] and also epilepsy [14], and for neuroprotection against brain injury [15]. A2A receptor antagonists, such as istradefylline, are close to being used to treat Parkinson’s disease [16] and Huntington’s disease [17].

Purinergic compounds are

Cardiovascular diseases

Purinergic signalling is being explored for the treatment of heart diseases, including infarction, arrhythmias, tachycardia, cardiomyopathies and angina (see [26]). The roles of A1, A2A, A2B and A3 receptors, as well as P2Y4, P2Y6, P2Y12, P2Y11, P2X3, P2X4 and P2X7 receptors have all been explored for heart diseases, but apart from the use of adenosine (Adenocard) via A1 receptors for the treatment of supraventricular tachycardia, their therapeutic potential is not resolved yet.

The therapeutic

Diseases of the airways

Purinergic signalling is being actively explored for the treatment of diseases of the airways (see [36], [37]), including asthma, where both A2A receptors [38] and P2X7 in particular [39] were shown to be involved in human studies, but the potential of A1, P2Y1, P2Y6 and P2X1 receptors are also being explored, as well as novel xanthine derivatives as potent and selective A2B receptor antagonists for the treatment of asthma [40]. For the treatment of chronic obstructive pulmonary disease, P2Y2

Diseases of the special senses

The early literature about purinergic signalling in the special senses was reviewed [52].

Immune system and inflammation

P2X7, P2Y1 and P2Y2 receptors expressed by inflammatory and immune cells play a pivotal role in immunomodulation and inflammation. The purinergic contribution to these events has been discussed in recent reviews [63], [64]. A2AR and P2Y12 receptors are also involved [65], [66]. In particular, P2X7 receptor antagonists, such as oxidized ATP, have been investigated in preclinical models of autoimmune diseases and tissue transplantation [67].

Infection

Multiple P1 and P2 receptors are expressed on immune cells and ATP has different actions depending on the receptors activated. For instance ATP has cytotoxic actions on macrophages via P2X7R, is bacteriocidal together with UTP via P2Y2R. P2X7 receptors are also involved in infectious, inflammatory and autoimmune diseases [68], [69] and in both bacterial (Escherichia coli) [70] and viral (Dengue virus-2) [71] infections. P2X7 receptors also play a key role in control of parasites such as

Diabetes

P2Y receptor agonists, including adenosine-5′-O-(2-thiodiphosphate), have been developed for the treatment of type 2 diabetes following studies in rats [74] as well as A2A receptor agonists [75], [76] and uridine adenosine tetraphosphate (Up4A) [77]. P2X7 receptor antagonists are gaining attention as potential therapeutic agents for both type 1 and 2 diabetes [58], [78]. P2X3 receptor antagonists are proposed for the treatment of diabetic neuropathic pain, when in a study of diabetic rats

Obesity

A2A receptor antagonists reduce high fat diet-induced obesity in mice and show promise for therapeutic treatment of obesity [81]. UDP, acting via P2Y6 receptors in the hypothalamus, increases obesity, so P2Y6 receptor antagonists, such as MRS2578, are promising anti-obesity agents [82]. Following a study of cultured human visceral adipose tissue where inhibition of P2X7 receptors decreased levels of inflammatory cytokines, suggesting a therapeutic strategy to target inflammatory conditions in

Gut disorders

Purinergic signalling plays a major role in both the physiology and pathophysiology of the gut (see [84]). Investigations of purinergic compounds as therapeutic targets for gut disorders are in progress [85], [86], including ulcerative colitis, where P2X7 receptor antagonists such as A-438079 [87] and down-regulation of A3 receptor expression [88] was effective; Crohn’s disease, where P2X7 receptor antagonists, such as AZD-9056, are therapeutic in a mouse model of Crohn’s disease [89], but not

Diseases of the kidney

A recent review about purinergic signalling in kidney diseases is available [94]. The P2X7 receptor antagonist A438079 was effective against renal injury and failure in a mouse model [95]; polycystic kidney disease, where the P2X7 receptor antagonist oxidized ATP reduced cyst formation in a zebrafish model [96]; ischaemia, where the role of adenosine in protection from renal ischaemia-reperfusion injury has been discussed [97]; nephritis, where again P2X7 receptor antagonists have therapeutic

Diseases of the lower urinary tract

The early literature has been thoroughly reviewed [103]. Diseases include: overactive bladder, where P2X3 receptor antagonists, such as AF-742, are being considered for the treatment of both overactive bladder and bladder pain (see [104]); interstitial cystitis, both A1 receptor antagonists, for example DPCPX [105], and P2X7 receptor antagonists have been considered for the treatment of interstitial cystitis; outflow obstruction; bladder pain, P2X3 receptor antagonists are effective in reducing

Diseases of the liver

There are reviews concerned with purinergic signalling in liver diseases [108], [109], [110]. These include: fibrosis, where blockade of the P2X7 receptor/NLRP3 inflammasome axis in cultured hepatic stellate cells with A438079 was considered a novel therapeutic target for liver fibrosis [111]; cirrhosis, both A1 and A2A receptor agonists have been claimed to reduce cirrhosis; cancer, P2X3 and P2Y11 receptor antagonists and A3 receptor agonists have each been claimed to inhibit liver metastasis;

Diseases of the reproductive system

There is a review concerned with purinergic signalling in the reproductive tract in health and disease [112]. These include: erectile dysfunction, P2Y1 and P2Y4 receptor agonists have been suggested for treatment of erectile dysfunction following both animal and human studies [113], [114]. It has also been suggested that P2X3 receptor antagonists may improve recovery of erectile function, when suramin proved to be efficacious in a rat model of erectile dysfunction [115]; prostatic hyperplasia;

Skin diseases

Reviews concerned with purinergic signalling in the skin have been published [120], [121]. Psoriasis, the use of A3 receptor agonists, such as CF101 that is undergoing clinical trials, for the treatment of psoriasis has been explored [122], [123] and A2A receptor antagonists, including SCH-442416 [124] and A2B receptor agonists, such as BAY60e6583 [125] are also being considered, as well as the involvement of P2Y1, P2Y2, P2Y11 and P2X7 receptors. Scleroderma, A2A receptors have been suggested

Musculoskeletal diseases

Reviews have been published that include the roles of purinergic signalling in musculoskeletal diseases [135], [136], [137]. Muscular dystrophy, it was suggested that P2Y2 receptor antagonists may ameliorate cardiomyopathy in Duchenne muscular dystrophy, since suramin reduced cardiomyopathy in a mouse model [138]. P2X4 and P2X7 receptors are expressed on dystrophic myoblasts and following a study of the dystrophic mdx mouse it was suggested that P2X7 receptor antagonists (in particular

Concluding comments

The development of purinergic compounds for the treatment of a wide variety of diseases is still in its infancy, although P2Y12 receptor antagonists for the treatment of thrombosis and stroke, long lasting P2Y2 receptor agonists for the treatment of dry eye and A1 receptor agonists for supraventricular tachycardia are already well established. P2X3 receptor antagonists for chronic cough, visceral pain and hypertension are currently in clinical trials and further possible uses of purinergic

Conflict of interest and funding statements

The author declares that there is no conflict of interest. GB had no funding for the writing of this article.

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