Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism

Figures & data

Figure 1. Functionally important binding sites aligned on full-length P2X7 structure. (a) full-length structures of rat P2X7 in the putative closed (Apo, 6U9V) and open (ATP, 6U9W) states. (b,c) top-down (top) and side-on (bottom) views of the three, inter-subunit, ATP binding sites (B, ATP), and single orthosteric binding sites (B) and allosteric binding sites (C). (d) side-on view of a single P2X7 channel subunit (6U9V) to highlight locations of relevant binding sites and functionally important features.

Four sets of images of high-resolution crystal structures of the P2X7 ion channel with top-down and side-on views showing the channel in nine different ligand-bound states.

Table 1. P2X7 agonists, antagonists, and modulators: effects on function and/or expression.

Modulation	Ligand/Stimuli	P2X7 investigation Techniques
		Binding assay	Current recording	Ca2^+ influx	Dye uptake	IL-1β release	P2X7 expression
Agonist	ATP		EC50 = 780 µM Xenopus oocytes [31]	pEC50 = 4.13 1321N1 [32]	pEC50 = 4.94 1321N1 [32]
	BzATP		EC50 = 52 µM Xenopus oocytes [31]	pEC50 = 5.33 1321N1 [32]	pEC50 = 6.18 1321N1 [32]
	Histone		At >3 µg/ml Xenopus oocytes [33]
	LL-37			At 5 µM HEK293 [34]	At 5 µM HEK293 [34]	At 10 µM monocytes [35]
	HNP-1	- GST pull-down assay - Antibody assay: Co-localization on HEK-293 [36]			At 50 µg/ml HNP-1 [36]	At 50 µg/ml HNP-1 [36]
	hβD2				At 20 μg/mL HNP-1 [37]	AT 20 μg/mL HNP-1 [37]
	SAA					At 30 μg/mL Macrophage [38]
Antagonists	A438079	Ki = 68 nM Displacement of [3 H]-A-804598 [39]	IC50 = 493 nM HEK293 [40]	IC50 = 123 nM HEK293 [41]	IC50 = 300 nM HEk293 [42]	IC50 = 150 nM THP1 [39]
	A740003	Ki = 130 nM Displacement of [3 H]-A-804598 [39]		IC50 = 39.8 HEK293 [43]	IC50 = 92 nM THP1 [44]	IC50 = 156 nM THP1 [44]
	A804598	Ki = 8.9 nM [3 H]-A-804598 [39]		IC50 = 32 nM HEK293 [39]	IC50 = 93 nM THP1 [45]	IC50 = 9 nM THP1 [45]
	A839977			IC50 = 20 nM 1321N1 [46]	IC50 = 6.61 nM THP1 [46]	IC50 = 20 nM THP1 [46]
	AZ10606120	Kd = 1.4 nM [^3H]-AZ10606120 [47]	IC50 = 10 nM Xenopus oocytes [48]		IC50 = 10 nM THP1 [49]
	AZ11645373		IC50 = 31 nM HEK293 [40]		IC50 = 19.9 nM THP1 [49]	IC50 = 90 nM THP1 [50]
	AZ11657312				IC50 = 474 nM HEK293 [51]
	GSK1370319A	Ki = 176 nM Displacement of [3 H]-A-804598 [51]				IC50 = 3.2 nM Glial cell [52]
	GW791343				pIC50 = 7.2 HEK293 [53]
	ITH15004				IC50 = 9000 nM HEK293 [54]
	JNJ-47965567	Ki = 12.59 nM Displacement of [3 H]-A804598 [55]		IC50 = 35 nM HEK293 [56]	IC50 = 15.85 nM HEK293 [56]	IC50 = 25.12 nM PBMC [55]
	Brilliant blue G		IC50 = 10 nM HEK293 [57]	IC50 >10000 nM HEK293 [39]	pIC50 = 5.71 1321N1 [32]	IC50 = 700 nM THP1 [39]
	KN62			pIC50 = 4.97 1321N1 [32]	IC50 = 175 nM HEK293 [58]	IC50 = 12.59 nM THP1 [59]
	Lu AF27139	Ki = 55 nM Displacement of [3 H]-A-804598 [39]		IC50 = 55 nM HEK293 [39]		IC50 = 38 nM THP1 [39]
Expression	oxLDL						Increase [60]
	High glucose						Increase [61]
	Shear stress						Increase [62]
	Hypoxia						Increase [63,64] Decrease [65]
	Cell death, and aging						Increase [66,67]
	Physical exercise						Decrease [68]
	Interleukins, cytokines, TNF-alpha and LPS						Increase [69,70]
	Aβs						Increase [71]

Table 2. P2X7-selective and nonselective antagonist co-crystals.

Non-selective P2X inhibitors	Inhibit Histone Current?	P2X7 co-crystal	Ref
Suramin	Yes	NA	[133]
Reactive Blue 2	–	NA	[134]
TNP-ATP (Orthostatic inhibitors)	Yes	5XW6/chicken	[135]
PPNDS (Orthostatic inhibitors)	–	8JV8/Panda	[14]
PPADS (Orthostatic inhibitors)	Yes	8JV7/Panda	[14]
P2X7-selective inhibitors
A438079	No	NA	[136]
A740003	–	5U1U/Panda	[13]
A804598	–	5U2H (ATP bound)/Panda	[13]
A804598	–	5U1V/Panda	[13]
A839977	–	NA	[137]
AZ10606120	No	5U1W/Panda	[13]
AZ11645373	No	*Functionally Mapped	[15,138]
AZ11657312	–	NA	[139]
GSK1370319A	–	NA	[51]
GW791343	No	5U1Y/Panda	[13]
ITH15004	–	NA	[54]
JNJ-47965567	–	5U1X/Panda	[13]
JNJ-47865567	–	NA	[140]
JNJ-42253432	–	NA	[141]
JNJ-54166060	–	NA	[140]
LuAF27139	–	NA	[39]
Brilliant blue G	–	*Functionally Mapped	[15,57]
KN62	No	*Functionally Mapped	[15,142]
Radio labeled P2X7-selective inhibitors
[11C] JNJ-54173717	–	NA	[143]
[3 H] JNJ-54232334	–	NA	[144]
[11C] GSK1482160	–	NA	[145]

Table 3. P2X7 inhibitors in clinical trials.

Compound	Indication	Phase	Results	Company	NCT Number	Ref
JNJ-54175446	Major depression	II	NA	Janssen Pharmaceuticals	NCT04116606	[151]
JNJ-55308942	Bipolar depression	II	NA	Janssen Pharmaceuticals	NCT05328297	[152]
PTM-001	Hidradenitis Suppurativa	II	NA	Phoenicis Therapeutics	NCT05020730	[152]
CE-224,535	Rheumatoid arthritis	II	No effect	Pfizer	NCT00628095	[153]
AZD-9056	Rheumatoid Arthritis	II	No effect	AstraZeneca	NCT00520572	[154]
GSK1482160	Inflammatory pain	I	No effect	GlaxoSmithKline	NCT00849134	[155]
BSCT (Anti-nf-P2X7)	Basal Cell Carcinoma	I	Reduced BCC size	Biosceptre	NCT02587819	[156]
SGM-1019	Non-alcoholic steatohepatitis	II	Unfavorable risk/benefit	Second Genome	NCT03676231	[157]
[18F] JNJ-64413739	Glioblastoma/Diagnostic test: PET imaging	NA	NA	Janssen Pharmaceuticals	NCT05753995	[156]

Jacobson KA, Jarvis MF, Williams M. Purine and pyrimidine (P2) receptors as drug targets. J Med Chem. 2002 Sep 12;45(19):4057–4093. doi: 10.1021/jm020046y

 PubMed Web of Science ®Google Scholar

Donnelly-Roberts DL, Namovic MT, Han P, et al. Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors. Br J Pharmacol. 2009 Aug;157(7):1203–1214. doi: 10.1111/j.1476-5381.2009.00233.x

 PubMed Web of Science ®Google Scholar

Al-Aqtash R, Ross MS, Collier DM. Extracellular histone proteins activate P2XR7 channel current. JGP. 2023;155(7). doi: 10.1085/jgp.202213317

 Google Scholar

Tomasinsig L, Pizzirani C, Skerlavaj B, et al. The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner. J Biol Chem. 2008 Nov 7;283(45):30471–30481. doi: 10.1074/jbc.M802185200

 PubMed Web of Science ®Google Scholar

Elssner A, Duncan M, Gavrilin M, et al. A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1β processing and release. J Immunol. 2004;172(8):4987–4994. doi: 10.4049/jimmunol.172.8.4987

 PubMed Web of Science ®Google Scholar

Chen Q, Jin Y, Zhang K, et al. Alarmin HNP-1 promotes pyroptosis and IL-1β release through different roles of NLRP3 inflammasome via P2X7 in LPS-primed macrophages. Innate Immun. 2014 Apr;20(3):290–300. doi: 10.1177/1753425913490575

 PubMed Web of Science ®Google Scholar

Wang P, Li G, Gao L, et al. Human β-defensin 2 enhances IL-1β production and pyroptosis through P2X7-mediated NLRP3 expression in macrophages. Biocell. 2022;46(5):1197–1207. doi: 10.32604/biocell.2022.016607

 Web of Science ®Google Scholar

Niemi K, Teirilä L, Lappalainen J, et al. Serum amyloid a activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011 Jun 1;186(11):6119–6128. doi: 10.4049/jimmunol.1002843

 PubMed Web of Science ®Google Scholar

Hopper AT, Juhl M, Hornberg J, et al. Synthesis and characterization of the novel rodent-active and CNS-Penetrant P2X7 receptor antagonist Lu AF27139. J Med Chem. 2021 Apr 22;64(8):4891–4902. doi: 10.1021/acs.jmedchem.0c02249

 PubMed Web of Science ®Google Scholar

Bradley HJ, Browne LE, Yang W, et al. Pharmacological properties of the rhesus macaque monkey P2X7 receptor. Br J Pharmacol. 2011 Sep;164(2b):743–754. doi: 10.1111/j.1476-5381.2011.01399.x

 PubMed Web of Science ®Google Scholar

Perez-Medrano A, Donnelly-Roberts DL, Florjancic AS, et al. Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine P2X(7) antagonists. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3297–3300. doi: 10.1016/j.bmcl.2011.04.024

 PubMed Web of Science ®Google Scholar

Kwak SH, Shin S, Lee JH, et al. Synthesis and structure-activity relationships of quinolinone and quinoline-based P2X7 receptor antagonists and their anti-sphere formation activities in glioblastoma cells. Eur J Med Chem. 2018 May 10;151:462–481. doi: 10.1016/j.ejmech.2018.03.023

 PubMed Web of Science ®Google Scholar

Perez-Medrano A, Donnelly-Roberts DL, Honore P, et al. Discovery and biological evaluation of novel cyanoguanidine P2X(7) antagonists with analgesic activity in a rat model of neuropathic pain. J Med Chem. 2009 May 28;52(10):3366–3376. doi: 10.1021/jm8015848

 PubMed Web of Science ®Google Scholar

Honore P, Donnelly-Roberts D, Namovic MT, et al. A-740003 [N-(1-{(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. J Pharmacol Exp Ther. 2006 Dec;319(3):1376–1385. doi: 10.1124/jpet.106.111559

 PubMed Web of Science ®Google Scholar

O’Brien-Brown J, Jackson A, Reekie TA, et al. Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X(7) receptor antagonists. Eur J Med Chem. 2017 Apr 21;130:433–439. doi: 10.1016/j.ejmech.2017.02.060

 PubMed Web of Science ®Google Scholar

Gonzaga DTG, Ferreira LBG, Moreira Maramaldo Costa TE, et al. 1-Aryl-1H- and 2-aryl-2H-1,2,3-triazole derivatives blockade P2X7 receptor in vitro and inflammatory response in vivo. Eur J Med Chem. 2017 Oct 20;139:698–717. doi: 10.1016/j.ejmech.2017.08.034

 PubMed Web of Science ®Google Scholar

Li RY, Guo L. Exercise in diabetic nephropathy: protective effects and molecular mechanism. Int J Mol Sci. 2024 Mar 23;25(7):3605. doi: 10.3390/ijms25073605

 PubMed Web of Science ®Google Scholar

Allsopp RC, Dayl S, Schmid R, et al. Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120. Sci Rep. 2017 Apr 7;7(1):725. doi: 10.1038/s41598-017-00732-5

 PubMedGoogle Scholar

Guile SD, Alcaraz L, Birkinshaw TN, et al. Antagonists of the P2X(7) receptor. From lead identification to drug development. J Med Chem. 2009 May 28;52(10):3123–3141. doi: 10.1021/jm801528x

 PubMed Web of Science ®Google Scholar

Stokes L, Jiang LH, Alcaraz L, et al. Characterization of a selective and potent antagonist of human P2X(7) receptors, AZ11645373. Br J Pharmacol. 2006 Dec;149(7):880–887. doi: 10.1038/sj.bjp.0706933

 PubMed Web of Science ®Google Scholar

Homerin G, Jawhara S, Dezitter X, et al. Pyroglutamide-based P2X7 receptor antagonists targeting inflammatory bowel disease. J Med Chem. [2020 Mar 12];63(5):2074–2094. doi: 10.1021/acs.jmedchem.9b00584

 PubMed Web of Science ®Google Scholar

Murphy N, Cowley TR, Richardson JC, et al. The neuroprotective effect of a specific P2X₇ receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells. Brain Pathol. 2012 May;22(3):295–306. doi: 10.1111/j.1750-3639.2011.00531.x

 PubMed Web of Science ®Google Scholar

Michel AD, Chambers LJ, Walter DS. Negative and positive allosteric modulators of the P2X(7) receptor. Br J Pharmacol. 2008 Feb;153(4):737–750. doi: 10.1038/sj.bjp.0707625

 PubMed Web of Science ®Google Scholar

Calzaferri F, Narros-Fernández P, de Pascual R, et al. Synthesis and pharmacological evaluation of novel non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation. J Med Chem. 2021 Feb 25;64(4):2272–2290. doi: 10.1021/acs.jmedchem.0c02145

 PubMed Web of Science ®Google Scholar

Letavic MA, Lord B, Bischoff F, et al. Synthesis and pharmacological characterization of two novel, brain penetrating P2X7 antagonists. ACS Med Chem Lett. 2013 Apr 11;4(4):419–422. doi: 10.1021/ml400040v

 PubMed Web of Science ®Google Scholar

Patberg M, Isaak A, Füsser F, et al. Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists. Eur J Med Chem. 2021 Dec 15;226:113838. doi: 10.1016/j.ejmech.2021.113838

 PubMed Web of Science ®Google Scholar

Jiang LH, Mackenzie AB, North RA, et al. Brilliant blue G selectively blocks ATP-gated rat P2X(7) receptors. Mol Pharmacol. 2000 Jul;58(1):82–88. doi: 10.1124/mol.58.1.82

 PubMed Web of Science ®Google Scholar

Lee GE, Joshi BV, Chen W, et al. Synthesis and structure-activity relationship studies of tyrosine-based antagonists at the human P2X7 receptor. Bioorg Med Chem Lett. 2008 Jan 15;18(2):571–575. doi: 10.1016/j.bmcl.2007.11.077

 PubMed Web of Science ®Google Scholar

Park JH, Lee GE, Lee SD, et al. Discovery of novel 2,5-dioxoimidazolidine-based P2X(7) receptor antagonists as constrained analogues of KN62. J Med Chem. 2015 Mar 12;58(5):2114–2134. doi: 10.1021/jm500324g

 PubMed Web of Science ®Google Scholar

Yang M, Qiu R, Wang W, et al. P2X7 receptor antagonist attenuates retinal inflammation and neovascularization induced by oxidized low-density lipoprotein. Oxid Med Cell Longev. 2021;2021:1–18. doi: 10.1155/2021/5520644

 Web of Science ®Google Scholar

Liu C, Tian Q, Wang J, et al. Blocking P2RX7 attenuates ferroptosis in endothelium and reduces HG-induced hemorrhagic transformation after MCAO by Inhibiting ERK1/2 and P53 signaling pathways. Mol Neurobiol. 2023 Feb;60(2):460–479. doi: 10.1007/s12035-022-03092-y

 PubMedGoogle Scholar

Green JP, Souilhol C, Xanthis I, et al. Atheroprone flow activates inflammation via endothelial ATP-dependent P2X7-p38 signalling. Cardiovasc Res. 2018 Feb 1;114(2):324–335. doi: 10.1093/cvr/cvx213

 PubMed Web of Science ®Google Scholar

Franke H, Günther A, Grosche J, et al. P2X7 receptor expression after ischemia in the cerebral cortex of rats. J Neuropathol Exp Neurol. 2004;63(7):686–699. doi: 10.1093/jnen/63.7.686

 PubMed Web of Science ®Google Scholar

Li X, Hu B, Wang L, et al. P2X7 receptor-mediated phenotype switching of pulmonary artery smooth muscle cells in hypoxia. Mol Biol Rep. 2021;48(3):2133–2142. doi: 10.1007/s11033-021-06222-2

 PubMed Web of Science ®Google Scholar

Wang LY, Cai WQ, Chen PH, et al. Downregulation of P2X7 receptor expression in rat oligodendrocyte precursor cells after hypoxia ischemia. Glia. 2009;57(3):307–319. doi: 10.1002/glia.20758

 PubMed Web of Science ®Google Scholar

Ponnusamy M, Liu N, Gong R, et al. ERK pathway mediates P2X7 expression and cell death in renal interstitial fibroblasts exposed to necrotic renal epithelial cells. Am J Physiol Renal Physiol. 2011 Sep;301(3):F650–9. doi: 10.1152/ajprenal.00215.2011

 PubMed Web of Science ®Google Scholar

Chen Y, Li G, Huang LY. P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol Pain. 2012 Feb 7;8:9. doi: 10.1186/1744-8069-8-9

 PubMed Web of Science ®Google Scholar

Comassi M, Santini E, Rossi C, et al. The level of physical training modulates cytokine levels through P2X7 receptor in healthy subjects. Eur J Clin Invest. 2018;48(2):e12880. doi: 10.1111/eci.12880

 Web of Science ®Google Scholar

Zhang XJ, Zheng GG, Ma XT, et al. Effects of various inducers on the expression of P2X7 receptor in human peripheral blood mononuclear cells. Sheng Li Xue Bao. 2005 Apr 25;57(2):193–198.

 PubMedGoogle Scholar

Humphreys BD, Dubyak GR. Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes. J Leukocyte Biol. 1998 Aug;64(2):265–273. doi: 10.1002/jlb.64.2.265

 PubMed Web of Science ®Google Scholar

Martínez-Frailes C, Di Lauro C, Bianchi C, et al. Amyloid peptide induced neuroinflammation increases the P2X7 receptor expression in microglial cells, impacting on its functionality. Front Cell Neurosci. 2019;13:143. doi: 10.3389/fncel.2019.00143

 PubMed Web of Science ®Google Scholar

Hedden L, Benes CH, Soltoff SP. P2X7 receptor antagonists display agonist-like effects on cell signaling proteins. Biochim Biophys Acta Gen Subj. 2011 05 01;1810(5):532–542. doi: 10.1016/j.bbagen.2011.03.009

 Web of Science ®Google Scholar

Melani A, Amadio S, Gianfriddo M, et al. P2X7 receptor modulation on microglial cells and reduction of brain infarct caused by middle cerebral artery occlusion in rat. J Cereb Blood Flow Metab. 2006;26(7):974–982. doi: 10.1038/sj.jcbfm.9600250

 PubMed Web of Science ®Google Scholar

Kasuya G, Yamaura T, Ma XB, et al. Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel. Nat Commun. 2017 Oct 12;8(1):876. doi: 10.1038/s41467-017-00887-9

 PubMedGoogle Scholar

Dy S, Chenqian Y, Jin F, et al. Structural insights into the orthosteric inhibition of P2X receptors by non-ATP-analog antagonists. Elife. 2023.

 Web of Science ®Google Scholar

Donnelly-Roberts DL, Jarvis MF. Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. Br J Pharmacol. 2007 Jul;151(5):571–579. doi: 10.1038/sj.bjp.0707265

 PubMed Web of Science ®Google Scholar

Karasawa A, Kawate T. Structural basis for subtype-specific inhibition of the P2X7 receptor. Elife. 2016 Dec 9;5. doi: 10.7554/eLife.22153

 PubMed Web of Science ®Google Scholar

Honore P, Donnelly-Roberts D, Namovic M, et al. The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice. Behav Brain Res. 2009 Dec 1;204(1):77–81. doi: 10.1016/j.bbr.2009.05.018

 PubMed Web of Science ®Google Scholar

Bin Dayel A, Evans RJ, Schmid R. Mapping the site of action of human p2x7 receptor antagonists AZ11645373, brilliant blue G, KN-62, calmidazolium, and ZINC58368839 to the intersubunit allosteric pocket. Mol Pharmacol. 2019 Sep;96(3):355–363. doi: 10.1124/mol.119.116715

 PubMed Web of Science ®Google Scholar

Michel AD, Ng SW, Roman S, et al. Mechanism of action of species-selective P2X(7) receptor antagonists. Br J Pharmacol. 2009 Apr;156(8):1312–1325. doi: 10.1111/j.1476-5381.2009.00135.x

 PubMed Web of Science ®Google Scholar

Menzies RI, Howarth AR, Unwin RJ, et al. Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats. Kidney Int. 2015 Nov;88(5):1079–1087. doi: 10.1038/ki.2015.182

 PubMed Web of Science ®Google Scholar

Bhattacharya A, Wang Q, Ao H, et al. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br J Pharmacol. 2013 Oct;170(3):624–640. doi: 10.1111/bph.12314

 PubMed Web of Science ®Google Scholar

Lord B, Aluisio L, Shoblock JR, et al. Pharmacology of a novel central nervous system-penetrant P2X7 antagonist JNJ-42253432. J Pharmacol Exp Ther. 2014 Dec;351(3):628–641. doi: 10.1124/jpet.114.218487

 PubMed Web of Science ®Google Scholar

Gargett CE, Wiley JS. The isoquinoline derivative KN-62 a potent antagonist of the P2Z-receptor of human lymphocytes. Br J Pharmacol. 1997 Apr;120(8):1483–1490. doi: 10.1038/sj.bjp.0701081

 PubMed Web of Science ®Google Scholar

Van Weehaeghe D, Koole M, Schmidt ME, et al. [(11)C]JNJ54173717, a novel P2X7 receptor radioligand as marker for neuroinflammation: human biodistribution, dosimetry, brain kinetic modelling and quantification of brain P2X7 receptors in patients with Parkinson’s disease and healthy volunteers. Eur J Nucl Med Mol Imaging. 2019 Sep;46(10):2051–2064. doi: 10.1007/s00259-019-04369-6

 PubMed Web of Science ®Google Scholar

Lord B, Ameriks MK, Wang Q, et al. A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334. Eur J Pharmacol. 2015 Oct 15;765:551–559. doi: 10.1016/j.ejphar.2015.09.026

 PubMed Web of Science ®Google Scholar

Gao M, Wang M, Green MA, et al. Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor. Bioorganic Med Chem Lett. 2015 May 01;25(9):1965–1970. doi: 10.1016/j.bmcl.2015.03.021

 PubMed Web of Science ®Google Scholar

Recourt K, de Boer P, van der Ark P, et al. Characterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder. Transl Psychiatry. 2023 Jul 24;13(1):266. doi: 10.1038/s41398-023-02557-5

 PubMed Web of Science ®Google Scholar

Bhattacharya A, Lord B, Grigoleit JS, et al. Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia. Neuropsychopharmacology. 2018 Dec;43(13):2586–2596. doi: 10.1038/s41386-018-0141-6

 PubMed Web of Science ®Google Scholar

Stock TC, Bloom BJ, Wei N, et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol. 2012 Apr;39(4):720–727. doi: 10.3899/jrheum.110874

 PubMed Web of Science ®Google Scholar

Keystone EC, Wang MM, Layton M, et al. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis. 2012 Oct;71(10):1630–1635. doi: 10.1136/annrheumdis-2011-143578

 PubMed Web of Science ®Google Scholar

Ali Z, Laurijssens B, Ostenfeld T, et al. Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects. Br J Clin Pharmacol. 2013 Jan;75(1):197–207. doi: 10.1111/j.1365-2125.2012.04320.x

 PubMed Web of Science ®Google Scholar

Gilbert SM, Gidley Baird A, Glazer S, et al. A phase I clinical trial demonstrates that nfP2X(7) -targeted antibodies provide a novel, safe and tolerable topical therapy for basal cell carcinoma. Br J Dermatol. 2017 Jul;177(1):117–124. doi: 10.1111/bjd.15364

 PubMed Web of Science ®Google Scholar

Baeza-Raja B, Goodyear A, Liu X, et al. Pharmacological inhibition of P2RX7 ameliorates liver injury by reducing inflammation and fibrosis. PLoS One. 2020;15(6):e0234038. doi: 10.1371/journal.pone.0234038

 PubMed Web of Science ®Google Scholar

Data availability statement

Data sharing is not applicable to this article as no new data were created in this study.