Antagonists of the P2X<sub>7</sub> Receptor. From Lead Identification to Drug Development

Guile, Simon D.; Alcaraz, Lilian; Birkinshaw, Timothy N.; Bowers, Keith; Ebden, Mark R.; Furber, Mark; Stocks, Michael J.

doi:10.1021/jm801528x

Cited by 132 publications

(98 citation statements)

References 59 publications

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“…Of those, a considerable fraction relates to immunological and neoplastic processes. Consequently, the P2X7 has become an appealing target for pharmacological intervention, and efforts have been made to develop novel P2X7-selective antagonists as new research tools [22][23][24]. Owing to its strong expression in certain leucocyte lineages, P2X7 is known for mediating effects of ATP on the secretion of pro-inflammatory cytokines [3,9,25].…”

Section: Discussionmentioning

confidence: 99%

Natural compounds with P2X7 receptor-modulating properties

Fischer

Urban

Immig

et al. 2013

Purinergic Signalling

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The adenosine 5′-triphosphate (ATP)-gated P2X7 receptor is a membrane-bound, non-selective cation channel, expressed in a variety of cell types. The P2X7 senses high extracellular ATP concentrations and seems to be implicated in a wide range of cellular functions as well as pathophysiological processes, including immune responses and inflammation, release of gliotransmitters and cytokines, cancer cell growth or development of neurodegenerative diseases. In the present study, we identified natural compounds and analogues that can block or sensitize the ATP (1 mM)-induced Ca 2+ response using a HEK293 cell line stably expressing human P2X7 and fluorometric imaging plate reader technology. For instance, teniposide potently blocked the human P2X7 at sub-miromolar concentrations, but not human P2X4 or rat P2X2. A marked block of ATPinduced Ca 2+ entry and Yo-Pro-1 uptake was also observed in human A375 melanoma cells and mouse microglial cells, both expressing P2X7. On the other hand, agelasine (AGL) and garcinolic acid (GA) facilitated the P2X7 response to ATP in all three cell populations. GA also enhanced the YO-PRO-1 uptake, whereas AGL did not affect the ATP-stimulated intracellular accumulation of this dye. According to the pathophysiological role of P2X7 in various diseases, selective modulators may have potential for further development, e.g. as neuroprotective or antineoplastic drugs.

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Section: Discussionmentioning

confidence: 99%

Natural compounds with P2X7 receptor-modulating properties

Fischer

Urban

Immig

et al. 2013

Purinergic Signalling

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“…Another P2X 7 receptor antagonist, A-438079, selectively blocks the P2X 7 receptor, 34 and shows a high degree of selectivity for P2X 7 in humans, rats and mice. 10,17,18 Within 4 weeks of treatment, BBG markedly attenuated salt-sensitive hypertension, urinary protein excretion, interstitial fibrosis and macrophage and T-cell infiltration in DS rats that received the high-salt diet. A-438079 treatment for 7 days also significantly attenuated 24-h urinary albumin excretion and macrophage infiltration in the DS rats fed the high-salt diet.…”

Section: P2x 7 Expression Is Higher In the Kidneys Of Ds Ratsmentioning

confidence: 98%

P2X7 receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats

Naito

Hirokawa

et al. 2011

Hypertens Res

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The P2X 7 receptor is a ligand-gated ion channel activated by extracellular ATP, and a common genetic variation in the P2X 7 gene significantly affects blood pressure. P2X 7 receptor expression is associated with renal injury and some inflammatory diseases. Brilliant blue G (BBG) is a selective rat P2X 7 receptor antagonist. In this study, to test whether BBG has protective effects on saltsensitive hypertension and renal injury, Dahl salt-sensitive (DS) rats fed an 8% NaCl diet were i.p. injected with BBG (50 mg kg À1 per day) for 4 weeks. We also tested another P2X 7 receptor antagonist, namely A-438079 (100 mg kg À1 per day), for 7 days. We found that P2X 7 antagonism markedly attenuated salt-sensitive hypertension, urinary protein or albumin excretion, renal interstitial fibrosis and macrophage and T-cell infiltration in the DS rats, and significantly improved creatinine clearance. In an in vitro experiment using macrophages, we showed that lipopolysaccharide (LPS)-primed macrophages from the DS rats released more interleukin-1 beta in response to BzATP, a P2X 7 receptor agonist, than the macrophages from Lewis rats, possibly due to higher P2X 7 expression in the DS rats. In conclusion, in vivo blockade of P2X 7 receptors attenuated salt-sensitive hypertension and renal injury in the DS rats. Thus, P2X 7 appears to be responsible for a vicious cycle of salt-sensitive hypertension and renal injury in the DS rats, through higher expression in the immune cells. Furthermore, P2X 7 antagonists can prevent the development of salt-sensitive hypertension and renal injury, thus confirming that the P2X 7 receptor is an important therapeutic target. INTRODUCTIONThe P2X 7 receptor is an adenosine-5¢-triphosphate (ATP)-gated cation channel that is expressed mainly in certain immune cells, including macrophages and lymphocytes. 1,2 Stimulation of P2X 7 is proinflammatory, resulting in the release of inflammatory cytokines, such as interleukin (IL)-1 beta (b) and IL-18 from macrophages 2-5 and IL-2 from T cells, 5-7 as well as changes in the plasma membrane lipid distribution and cell death by necrosis or apoptosis. 2,3 P2X 7 has been reported to be involved in various nephropathy models, such as glomerular injury caused by diabetes and hypertension, 8 unilateral ureteral obstruction 9 and glomerulonephritis. 10 Dahl salt-sensitive (DS) rats fed on a high-sodium diet characteristically develop attenuated pressure natriuresis, hypertension and progressive renal injury, and this model has been widely used to study salt-sensitive hypertension. 11,12 In a previous study, we performed a genome-wide quantitative trait locus mapping analysis for blood pressure by using F2 rats derived from DS and Lewis (LEW) rats, and we identified a region on chromosome 12 near the D12Arb6 marker that influenced blood pressure. 13 The P2X 7 gene is also near the D12Arb6 marker. A common genetic variation in the region of the P2X 7 gene significantly affects blood pressure in a Caucasian population. 14 Although the pathophysiology of hypertension...

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“…Further support for this idea comes from studies using P2X 7 R gene-deleted transgenic mice, which have demonstrated anti-inflammatory phenotypes and reduced pain sensitivity in models of neuropathic pain, arthritis, and other chronic inflammatory processes (10). Moreover, several highly selective and potent P2X 7 R antagonists have been identified recently, showing antinociceptive actions in animal models and significant attenuation of joint destruction in a model of rheumatoid arthritis (RA) in rats (10,11).…”

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confidence: 99%