AF-353 | Idotdo Signal

The therapeutic potential of purinergic signalling Geoffrey Burnstock

PII: S0006-2952(17)30504-X
DOI: http://dx.doi.org/10.1016/j.bcp.2017.07.016
Reference: BCP 12879

To appear in: Biochemical Pharmacology

Received Date: 21 June 2017
Accepted Date: 18 July 2017

Please cite this article as: G. Burnstock, The therapeutic potential of purinergic signalling, Biochemical Pharmacology (2017), doi: http://dx.doi.org/10.1016/j.bcp.2017.07.016

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.The therapeutic potential of purinergic signalling By Geoffrey Burnstock
Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street,
London NW3 2PF, UK
and Department of Pharmacology and Therapeutics, The University of Melbourne,
Melbourne, Australia
E-mail: [email protected]

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, 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 will summarise the topic, mostly referring to recent review articles.

Keywords

ATP, CNS, Heart, Liver, Kidney, Skin

Chemical compounds studied in this article

A-317491 (PubChem CID: 9829395); AF-219 (PubChem CID: 24764487); AF-353 (PubChem CID: 15953802); AZD-9056 (PubChem CID: 10161381); (2′(3′)-O-(4-
benzoylbenzoyl) adenosine 5′-triphosphate (PubChem CID: 115205); clopidogrel (PubChem CID: 60606); diadenosine pentaphosphate (PubChem CID: 440210); diquafosol (PubChem CID: 148197); MRS 2578 (PubChem CID: 16078986); ticagrelor (PubChem CID: 9871419).

1. 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 Figure 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 Figure 1b), bladder diseases and hypertension. I will now summarise, mostly with recent review articles, the studies taking place in diseases of nearly all the bodily systems (see reviews [5-7]).

2. 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 being explored for the treatment of psychiatric disorders

(see [18]), including the use of the xanthine derivative propentofylline for schizophrenia [19, 20], allopurinol and dipyridamole for bipolar disorder [21], A2A receptor antagonism with istradefylline for depression and anxiety [22, 23], where P2X7 and A2A receptors are again dominant therapeutic possibilities. Antagonists to P2X4 and P2X7 receptors expressed on microglia are effective against neuropathic pain [24]. Janssen have developed new, highly potent, brain penetrating triazolopyrazine-based P2X7 receptor antagonists for CNS-related diseases. In particular, JNJ-54232334 was shown to be orally bioavailable with good drug- like properties, including CNS penetration effectiveness. It was found to be effectiveness in animal models of depression, mania, and pain [25].

3. 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 potential for vascular diseases is clearer (see [27, 28]). For hypertension, the P2X3 receptor antagonist AF-353 looks promising [29]. A3, P2X1 and P2X7 receptor antagonists and P2Y1, P2Y2, P2Y4 and P1 receptor agonists are also being considered. Purinergic compounds for the treatment of atherosclerosis are being investigated, including AF-353 (P2X3/P2X2/3 receptor antagonist), AZD-9056 (P2X7 receptor antagonist) and CGS-21680 (A2A receptor agonist) (see [30]), as well as A2B, A3, P2Y1 and P2X4 receptor antagonists [31]. For thrombosis and stroke P2Y12 receptor antagonists, such as clopidogrel and ticagrelor, are in wide international use (see [32]). They are well tolerated, but there is a small risk of haemorrhage and caution has been advised in patients taking clopidogrel and proton pump inhibitors. Since clopidogrel requires activation following passage through the liver, it’s efficacy in patients can be subject to polymorphic variations (particularly carriers of a reduced-function CYP2C19 allele) [33], whereas ticagrelor, which does not require hepatic activation and is recommended for patients with the CYP2C19 allele. Exploration of P2X3 receptor antagonists for the treatment of migraine [34] and A2A receptor antagonists for coronary artery disease [35] is taking place.

4. 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 and P2X7 receptor involvement is under investigation (see [41]). Purinergic signalling is involved in airway infections and the use of P2X7 receptor antagonists for bacterial [42], viral [43] and parasitic [44] infections, although not in patients with tuberculosis as a polymorphism of the P2X7 receptor was reported to increase the possibility of recurrence of TB [45]. A protective role for A2B receptor signalling has been reported to counter ischaemic lung injury in a study on rats [46] and pulmonary fibrosis in a study on mice [47]. There are reviews concerned with purinergic signalling in cystic fibrosis [36, 48], where the roles of A2B, P2Y2, P2Y4, P2Y11 and P2X4/6 heteromultimer receptors are being explored for therapeutic potential. An association of P2X7, P2X4 and P2Y1 receptors with metastatic lung tumours in human subjects has been reported [49]. Ecto-5′-nucleotidase (CD73) inhibitors are currently being tested in clinical trials for the treatment of non-small cell lung cancer [50] where A2B receptors and CD73 were shown to have opposing, prognostic effects in both cultured cells and an animal model [50]. There is recent promise for the treatment of chronic cough with the P2X3 receptor antagonist, AF-219 [51]. When it was undergoing clinical trials, it was found to be mostly well tolerated, but with some subjects high doses were effective against chronic cough but had serious taste disturbances [51]. However, when much lower concentrations of AF-219 were used the side effect was lost, probably because P2X2/3 heteromeric receptors were involved, but chronic cough suppression persisted,

5. Diseases of the special senses

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

5.1. Eye

Reviews concerned with visual diseases are available [53, 54]. Diadenosine tetraphosphate has recently been claimed to be effective for the treatment of glaucoma following a study in mice [55]. Treatment for dry eye by a long lasting P2Y2 receptor agonist, diquafosol, is currently in therapeutic use in Japan [56] and is also recommended for the treatment of retinal
detachment. Diquafosol is well tolerated, although a small proportion of users have described some irritation and occasionally discharge from the eye. P2X7 receptor antagonists and P1 receptor agonists, such as INO-8875, have been implicated for the treatment of diabetic neuropathy and retinopathy [57, 58] , while P2X7 receptor activation may be a target for the treatment of macular degeneration [59].

5.2. Ear

The involvement of P2X2 receptors in diseases of the auditory system, including tinnitus, Ménières disease and noise stress, has been reviewed that highlights the recent identification of three missense mutations in the P2X2 receptor that may allow for the development of gene therapy to treat progressive and noise-induced hearing loss [60].

5.3. Olfactory organs

Olfactory epithelium is the main odour sensing site composed of millions of olfactory sensory neurons. These express multiple subtypes of P2X and P2Y receptors. Of particular interest is the P2X3 receptor, activation of which negatively modulated the odour response in a mouse study, suggesting a protective strategy for olfactory sensory neurons [61].

5.4. Tongue

ATP is a major transmitter in the taste system, acting mainly via P2X2/3 heteromultimer receptors. Knock out mice for both P2X2 and P2X3 receptors lack responses to all taste stimuli. Similarly, injection of the P2X3 receptor antagonist, AF-353, or application of the drug directly to the tongue of wild type mice inhibited taste nerve responses to all taste qualities in a dose-dependent fashion. Disruption of taste function was an unintentional consequence of therapeutic trials for pain and chronic cough using other P2X3 receptor antagonists, such as AF-219, which have some antagonist effect on P2X2/3 receptors [62].

6. 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].

7. 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 Leishmania amazonensis and Trichomonas vaginalis [72, 73].

8. 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 expression of P2X3 receptors in the midbrain periaqueductal gray was decreased, impairing the descending inhibitory system in modulating pain transmission and contributing to the development of mechanical allodynia [79]. P2X7 receptor polymorphisms are associated with more or less severe diabetic pain [80].

9. 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 metabolically unhealthy obese individuals [83].

10. 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 A438079 [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 diseas [89], but not in a human phase II study, where they were more effective for the treatment of chronic abdominal pain [90]; irritable bowel syndrome, where P2X3 receptor antagonists have been recommended for therapeutic treatment, as well as iberogast, a phytopharmacon targeting purine mechanisms [91, 92]; and diarrhoea and
constipation (see [93]).

11. 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 potential [98]; hypertension, where P2X7 receptor antagonism with BBG prevented the development of salt-sensitive hypertension in a rat model [99]; diabetic nephropathy, where both A2B receptor antagonists [100] and P2X7 receptor antagonists [101] have been targeted for the treatment of diabetic nephropathy; cancer, where the anthraquinone, emodin, inhibited the invasiveness of human embryonic kidney cancer cells by antagonising P2X7 receptors [102].

12. 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 bladder pain (see [106]); ureter obstruction, stones in the ureter cause extreme pain and P2X3 receptor antagonists look promising to reduce the pain [107].

13. Diseases of the liver

There are reviews concerned with purinergic signalling in liver diseases [108-110]. 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; hepatitis, P2X7 receptors appear to be a major

component in hepatitis C viral infection in a study of human peripheral blood mononuclear cells [43].

14. 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 an rat model of erectile dysfunction [115]; prostatic hyperplasia; cervical infection, P2X7 receptor agonists, ATP and 2′(3′)-O-(4-benzoylbenzoyl)ATP (BzATP), have been suggested for the treatment of cervical infections, being effective in animal studies [116]; prostate cancer; ATP and adenosine both inhibit the growth of human prostate cancer cells [117] (see Figure 2), probably via P2Y receptors. P2X7 receptors are a marker for prostate cancer. A3 receptor activation with IB- MECA inhibited proliferation of several prostate cancer cell lines [118]; breast cancer, P2Y6 receptor antagonists have been suggested as a therapeutic target for breast cancer metastasis since P2Y6 mRNA was shown to be increased in breast cancer cell lines and was correlated with reduced survival rates in women and inhibition of P2Y6 receptors in cell lines reduced migration [119].

15. 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 have 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 as a therapeutic target for the treatment and prevention of dermal fibrosis in scleroderma, since a selective A2A antagonist, ZM241385, reduced fibrosis in mice [126], but the use of several other P2 receptor subtype antagonists, including P2X7, are also being examined. Skin inflammation, P2X7 receptor agonists may reduce skin inflammation as P2X7 receptor knock out mice exhibited more pronounced tissue inflammation following L. amazonensis infection [72]. Wound healing, A2A and to a lesser extent A2B receptor agonists promote cutaneous wound healing [127]. ATP and UTP enhanced proliferation of a murine keratinocyte cell line via P2Y2 receptors [128]. Warts,
allergy, Hailey-Hailey disease and barrier function, the involvement of purinergic signalling in all these conditions is being explored. Pain, the P2X3 receptor antagonist, 2′(3′)-O-(2,4,6- trinitrophenyl) ATP, was reported to reduce thermal hyperalgesia in rats [129] as did the P2Y1 receptor antagonist, MRS2500 [130]. They are effective against inflamed and injured skin. Reviews with coverage of purinergic signalling and cutaneous pain have been published [131, 132]. Skin cancer, P2X1 and P2Y2 and P2X7 receptors are involved in ultraviolet genesis of both basal and squamous cell carcinoma, as well as melanoma [133]. Proliferation outweighs apoptotic cell death in skin cancers. BzATP, a potent P2X7 receptor agonist, inhibited the formation of skin carcinomas there was accelerated melanoma tumour progression in mice lacking P2X7 receptors [134]. The therapeutic potential of other purinoceptors, including A1, A3, P2Y1, P2Y6 and P2X5 receptors are also being explored.

16. Musculoskeletal diseases

Reviews have been published that include the roles of purinergic signalling in musculoskeletal diseases [135-137]. 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 A-438079) may also have therapeutic potential [139]. A review about purinoceptors in muscular dystrophy is available [140]. Myasthenia
gravis, it was suggested that A2A receptors may have therapeutic potential for the treatment of myasthenia gravis as the A2A receptor agonist CGS21680C ameliorated disease severity in a rat model [141]. Osteoporosis, P2X7 receptor antagonists, such as AZD9056, are being considered for the treatment of osteoporosis [142]. It has been suggested recently that P2X5 receptors may be a therapeutic target for the treatment for inflammatory bone loss following a study of mice osteoclasts, which showed that P2X5 receptors were highly expressed during osteoclast maturation [143]. P2Y13 receptor antagonists have also been recommended for the treatment of osteoporosis, as P2Y13 knock out mice were protected against ovariectomy- induced bone loss [144]. Skeletal pain that accompanies osteoporosis might be reduced by P2X2/3 receptor antagonists, such as AF-353 [145]. Osteoarthritis, A2A receptor agonists have been claimed to be a promising target for the treatment of osteoarthritis as mice lacking A2A receptors spontaneously develop osteoarthritis [146]. P2X7 receptor antagonists have also been recommended following a study of rats where AZD9056 reduced both pain and inflammation following the induction of osteoarthritis [147], as have P2Y1 and P2Y12 receptor agonists [148] and P2X3 and P2X2/3 receptor antagonists for reducing articular hyperalgesia [149]. Rheumatoid arthritis, targeting P2X7 receptors has been considered to be promising to treat rheumatoid arthritis and several clinical trials were undertaken by drug companied, including AstraZeneca (with AZD9056) and Pfizer (with CE-224,535). Both these compound failed in the trials, with AZD9056 failing to change expression of inflammatory biomarkers, so it was concluded that AZD9056 was not therapeutically useful for rheumatoid arthritis [150]. Both P2X1 and P2X3 receptor antagonists and A3 and A2A receptor agonists have also been investigated for the treatment of arthritis. Bone cancer/pain, the P2X3 and P2X2/3 receptor selective antagonist, A-317491, attenuated cancer-induced bone pain in mice [151] and P2X7 receptor antagonists were also suggested as targets for cancer bone pain, since A839977effectively reduced pain behaviours in a rat model of cancer-induced bone pain [152]. Stimulation by adenosine monophosphate-activated protein kinase was claimed to reduce bone cancer pain in rats [153].

17. 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 compounds for many other diseases are discussed in this review. P2X7 receptor antagonists, A2A receptor agonists and P2X3 receptor antagonists seem to be particularly promising for many diseases. There are problems in identifying purinergic antagonists for therapeutic use in that most purinoceptors, and in particular the P2X7 subtype, have many polymorphic variations which require different antagonists and there is a need for medicinal chemists to develop more purinergic compounds which are orally bioavailable and stable in vivo and, for diseases of the brain, also drugs that penetrate the blood brain barrier. The recent elucidation of the structures of the mammalian P2X7 receptor [154] and human P2Y12 receptor [155] should aid in this search. However, I believe that we can look to the future of purinergic compounds as therapeutic agents with optimism. 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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Figure 1. (a) Three P2 receptor subtypes, P2X1, P2Y1 and P2Y12, are involved in ADP- induced platelet activation. Clopidogrel is a P2Y12 receptor blocker that inhibits platelet aggregation and is in highly successful use for the treatment of thrombosis and stroke. A P2Y1 receptor antagonist, MRS 2500, inhibits shape change. (Reproduced from [26] with permission from the American Heart Association, Inc.) (b) Schematic representation of hypothesis for purinergic mechanosensory transduction in tubes (e.g. ureter, vagina, salivary and bile ducts, gut) and sacs (e.g. urinary and gall bladders, and lung). It is proposed that distension leads to release of ATP from epithelium lining the tube or sac, which then acts on P2X3 and/or P2X2/3 receptors on subepithelial sensory nerves to convey sensory/nociceptive information to the CNS. (Reproduced from [156] with permission from Blackwell Publishing.)

Figure 2. (a) Effect of ATP (1ml of 25 mM i.p.) on the growth of implanted DU145 tumour cells in vivo after 60 days initial growth; the lower mouse received ATP treatment vs. no treatment in the upper mouse; and (b) Effect of ATP (1ml of 25 mM i.p.) on the fractional growth of hormone refractory prostate cancer DU145 tumour cells in vivo after 60 days initial growth. (Reproduced from [157] with permission.) (c) Schematic diagram illustrating the different mechanisms by which P2 receptor subtypes might alter cancer cell function. P2Y1 and P2Y2 receptors could affect the rate of cell proliferation through altering the intracellular levels of cAMP by modulating adenylyl cyclase (AC) or by increasing intracellular calcium levels through the phospholipase C (PLC) pathway. P2X5 and P2Y11 receptor activation might switch the cell cycle from proliferation into a state of differentiation. The P2X7 receptor activates the apoptotic caspase enzyme system. (Reproduced from [158] with permission from Elsevier.)

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Examples of purinoceptor subtypes as therapeutic targets

Already in clinical use Clinical Trials ‘Proof of concept’ studies
A1 (Adenocard) → supraventricular tachycardia P2Y2 (Diquafosol) → dry eye
P2Y12 (Clopidogrel/Tricagrelor) → Thrombosis &
stroke A2A → Parkinson’s disease A3 → psoriasis
P2X3 → chronic cough; hypertension; visceral pain; hypertension; overactive bladder

P2X7 → atherosclerosis; infection; abdominal pain; atherosclerosis; infection; rheumatoid arthritis (failed during trials) A2A → scleroderma; coronary artery disease; neurodegenerative & psychiatric diseases

A2B → asthma

P2X3 → migraine; atherosclerosis P2X4 → neuropathic pain
P2X5 → inflammatory bone loss

P2X7 → neurodegenerative & psychiatric diseases; atherosclerosis; asthma; autoimmune diseases; ulcerative colitis/Crohn’s disease; renal disease; cancer

P2Y2 → cancer; muscular dystrophy

P2Y12 → osteoporosis