The microglial ATP‐gated ion channel P2X7 as a CNS drug target

Bhattacharya, Anindya; Biber, Knut

doi:10.1002/glia.23001

Cited by 221Adenosine and Purinergic SignalingNeuroinflammation and Neurodegeneration MechanismsPain Mechanisms and Treatments

The microglial ATP‐gated ion channel P2X7 as a CNS drug target

Bhattacharya, Anindya, Biber, Knut·2016·Glia

DOI 10.1002/glia.23001

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Abstract

Based on promising preclinical evidence, microglial P2X7 has increasingly being recognized as a target for therapeutic intervention in neurological and psychiatric diseases. However, despite this knowledge no P2X7‐related drug has yet entered clinical trials with respect to CNS diseases. We here discuss the current literature on P2X7 being a drug target and identify unsolved issues and still open questions that have hampered the development of P2X7 dependent therapeutic approaches for CNS diseases. It is concluded here that the lack of brain penetrating P2X7 antagonists is a major obstacle in the field and that central P2X7 is a yet untested clinical drug target. In the CNS, microglial P2X7 activation causes neuroinflammation, which in turn plays a role in various CNS disorders. This has resulted in a surge of brain penetrant P2X7 antagonists. P2X7 is a viable, clinically untested CNS drug target. GLIA 2016;64:1772–1787

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P2X7 receptor activation increases neuroinflammatory responses, which have been associated with neurodegenerative diseases, psychiatric disorders and stroke.
“Remarkably, P2X7 receptor activation increases neuroinflammatory responses, which have been associated with neurodegenerative diseases, psychiatric disorders and stroke [21, 92–95], as further discussed.”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [93]
P2X7R-mediated effects, mainly through activation of the neuroinflammatory response, have been involved in MDD, neurodegenerative diseases, schizophrenia, epilepsy, neuropathic pain, and brain injury.
“P2X7R-mediated effects, which mainly occurs through activation of the neuroinflammatory response, have been involved in MDD, neurodegenerative diseases, schizophrenia, epilepsy, neuropathic pain and brain injury [28,66,67,68].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [67]
P2X7R has been proposed to be a potential target for therapeutic intervention in mental disorders, due to its activity in neuroinflammatory processes, which are significantly involved in MDD, schizophrenia, epilepsy and neurodegenerative diseases.
“P2X7R has been proposed to be a potential target for therapeutic intervention in mental disorders, due to its activity in neuroinflammatory processes, which are significantly involved in MDD, schizophrenia, epilepsy and neurodegenerative diseases (e.g., multiple sclerosis, Huntington, Parkinson’s and Alzheimer’s disease) [66,67,68].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [67]
Brain penetrant P2X7R antagonists have been developed.
“Hence, brain penetrant P2X7R antagonists have been developed, and testing the clinical effects of these drugs in neuropsychiatric disorders is the next step [67,68].”
From P2X7 Receptor Signaling in Stress and Depression (2019) · cites this paper as [67]

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Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohnʼs Disease
Eser, A., Colombel, J., Rutgeerts, P. J., Vermeire, S., Vogelsang, H., Braddock, M., Persson, T., & Reinisch, W. (2015) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000514 · Cited by 138 · see citing works
Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer's disease
Ryu, J. K., & McLarnon, J. G. (2008) · NeuroReport · doi:10.1097/wnr.0b013e3283179333 · Cited by 134 · see citing works
Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus
Meng, X., Tan, L., Tan, M., Jiang, T., Tan, C., Li, M., Wang, H.-F., & Yu, J. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0212-5 · Cited by 131 · see citing works
Exacerbation of Experimental Autoimmune Encephalomyelitis in P2X7R−/− Mice: Evidence for Loss of Apoptotic Activity in Lymphocytes
Chen, L., & Brosnan, C. F. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3115 · Cited by 130 · see citing works
The P2X7 receptor antagonist Brilliant Blue G attenuates contralateral rotations in a rat model of Parkinsonism through a combined control of synaptotoxicity, neurotoxicity and gliosis
do Carmo, M. R. S., Menezes, A. P. F., Nunes, A. C. L., Pliássova, A., Rolo, A. P., Palmeira, C. M., Cunha, R. A., Canas, P. M., & de Andrade, G. M. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.01.045 · Cited by 129 · see citing works
Evidence for IL-1 receptor blockade as a therapeutic strategy for the treatment of depression.
Koo, J. W., & Duman, R. S. (2009) · PubMed · Cited by 128 · see citing works
Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors
Csölle, C., Baranyi, M., Zsilla, G., Kittel, Á., Gölöncsér, F., Illes, P., Papp, E., Vizi, E. S., & Sperlágh, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066547 · Cited by 128 · see citing works
Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection
Witting, A., Chen, L., Cudaback, E., Straiker, A. J., Walter, L. M., Rickman, B. H., Möller, T., Brosnan, C. F., & Stella, N. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510418103 · Cited by 125 · see citing works
Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT
Kataoka, A., Tozaki‐Saitoh, H., Koga, Y., Tsuda, M., & Inoue, K. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05744.x · Cited by 121 · see citing works
The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1αβ knockout mice
Honoré, P., Donnelly‐Roberts, D. L., Namovic, M. T., Zhong, C., Wade, C. L., Chandran, P., Zhu, C., Carroll, W. A., Perez‐Medrano, A., Iwakura, Y., et al. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2009.05.018 · Cited by 116 · see citing works
[3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors
Donnelly‐Roberts, D. L., Namovic, M. T., Surber, B. W., Vaidyanathan, S. X., Perez‐Medrano, A., Wang, Y., Carroll, W. A., & Jarvis, M. F. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.06.012 · Cited by 111 · see citing works
Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects
Ali, Z., Laurijssens, B. E., Ostenfeld, T., McHugh, S. M., Stylianou, A., Scott‐Stevens, P., Hosking, L. K., Dewit, O., Richardson, J. C., & Chen, C. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04320.x · Cited by 111 · see citing works
Central nervous system myeloid cells as drug targets: current status and translational challenges
Biber, K. P. H., Möller, T., Boddeke, E., & Prinz, M. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.14 · Cited by 111 · see citing works
Self-citation
Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test
Boucher, A. A., Arnold, J. C., Hunt, G. E., Spiro, A., Spencer, J., Brown, C., McGregor, I. S., Bennett, M. R., & Kassiou, M. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.05.049 · Cited by 108 · see citing works
The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice
Csölle, C., Andó, R. D., Kittel, Á., Gölöncsér, F., Baranyi, M., Soproni, K., Zelena, D., Haller, J., Németh, T., Mócsai, A., et al. (2013) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711001933 · Cited by 108 · cited 6× · see citing works
“…in a model of sucrose consumption that is reflective of hedonic behavior, pharmacological antagonism of P2X7 (by AZ-10606120 and A-804598) restored the deficit observed in drinking sucrosewater (anhedonia) either under chronic stress or by systemic administration of LPS (Csolle et al., 2013b).”
BackgroundInfluential
In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1β in the murine brain
Mingam, R., Smedt, V. D., Amédée, T., Bluthé, R.-M., Kelley, K. W., Dantzer, R., & Layé, S. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.08.007 · Cited by 107 · see citing works
Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases, Revealed by Structural Modeling and Single Nucleotide Polymorphisms
Jiang, L., Baldwin, J. M., Roger, S., & Baldwin, S. A. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00055 · Cited by 105 · see citing works
Purinergic receptor P2X7: A novel target for anti-inflammatory therapy
Mehta, N., Kaur, M., Singh, M., Chand, S., Vyas, B., Silakari, P., Bahia, M. S., & Silakari, O. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.10.054 · Cited by 103 · see citing works
Nonsynaptic and nonvesicular ATP release from neurons and relevance to neuron–glia signaling
Fields, R. D. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.02.009 · Cited by 103 · see citing works
Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors
Nörenberg, W., Sobottka, H., Hempel, C., Plötz, T., Fischer, W., Schmalzing, G., & Schaefer, M. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01987.x · Cited by 102 · see citing works
ATP Signaling in Brain: Release, Excitotoxicity and Potential Therapeutic Targets
Cisneros-Mejorado, A., Pérez‐Samartín, A., Gottlieb, M., & Matute, C. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0092-3 · Cited by 93 · see citing works
P2X7 Receptor Activation Induces Reactive Oxygen Species Formation and Cell Death in Murine EOC13 Microglia
Bartlett, R., Yerbury, J. J., & Sluyter, R. (2013) · Mediators of Inflammation · doi:10.1155/2013/271813 · Cited by 91 · see citing works
Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures
Hellwig, S., Masuch, A., Nestel, S., Katzmarski, N., Meyer-Luehmann, M., & Biber, K. (2015) · Scientific Reports · doi:10.1038/srep14624 · Cited by 91 · see citing works
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P2X7 receptor immunoreactive profile confined to resting and activated microglia in the epileptic brain
Rappold, P. M., Lynd‐Balta, E., & Joseph, S. (2006) · Brain Research · doi:10.1016/j.brainres.2006.03.040 · Cited by 90 · see citing works
Never-resting microglia: physiological roles in the healthy brain and pathological implications
Sierra, A., Tremblay, M., & Wake, H. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00240 · Cited by 88 · see citing works
Synthesis and initial preclinical evaluation of the P2X7 receptor antagonist [11C]A‐740003 as a novel tracer of neuroinflammation
Janssen, B., Vugts, D. J., Funke, U., et al. (2014) · Journal of Labelled Compounds and Radiopharmaceuticals · doi:10.1002/jlcr.3206 · Cited by 83 · see citing works
Probenecid Blocks Human P2X7 Receptor-Induced Dye Uptake via a Pannexin-1 Independent Mechanism
Bhaskaracharya, A., Dao‐Ung, P., Jalilian, I., Spildrejorde, M., Skarratt, K. K., Fuller, S. J., Sluyter, R., & Stokes, L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093058 · Cited by 81 · see citing works
Mechanism of microglia neuroprotection: Involvement of<scp>P2X</scp>7,<scp>TNF</scp>α, and valproic acid
Masuch, A., Shieh, C., van Rooijen, N., van Calker, D., & Biber, K. (2016) · Glia · doi:10.1002/glia.22904 · Cited by 81 · see citing works
Self-citation
Characterization of N-(Adamantan-1-ylmethyl)-5-[(3 R-aminopyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 Antagonist in Animal Models of Pain and Inflammation
Broom, D. C., Matson, D. J., Bradshaw, E., Buck, M. E., Meade, R., Coombs, S. E., Matchett, M., Ford, K. K., Yu, W., Yuan, J., et al. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.141853 · Cited by 79 · see citing works
Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535
Duplantier, A. J., Dombroski, M. A., Subramanyam, C., Beaulieu, A. M., Chang, S.-P., Gabel, C. A., Jordan, C. K., Kalgutkar, A. S. S., Kraus, K. G., Labasi, J. M., et al. (2011) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2011.04.077 · Cited by 78 · see citing works
Clemastine Potentiates the Human P2X7 Receptor by Sensitizing It to Lower ATP Concentrations
Nörenberg, W., Hempel, C., Urban, N. D., Sobottka, H., Illés, P., & Schaefer, M. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.198879 · Cited by 77 · see citing works
Synthesis of [11C]GSK1482160 as a new PET agent for targeting P2X7 receptor
Gao, M., Wang, M., Green, M. A., Hutchins, G. D., & Zheng, Q. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.03.021 · Cited by 77 · see citing works
Gain-of-function of P2X7 receptor gene variants in multiple sclerosis
Oyanguren-Desez, O., Antigüedad, A. R., Villoslada, P., Domercq, M., Alberdi, E. M., & Matute, C. (2011) · Cell Calcium · doi:10.1016/j.ceca.2011.08.002 · Cited by 75 · see citing works
Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage
Cisneros-Mejorado, A., Gottlieb, M., Cavaliere, F., Magnus, T. U., Koch‐Nolte, F., Scemes, E., Pérez‐Samartín, A., & Matute, C. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.262 · Cited by 75 · see citing works
P2X7 receptor activation regulates microglial cell death during oxygen-glucose deprivation
Eyo, U. B., Miner, S. A., Ahlers‐Dannen, K. E., Wu, L., & Dailey, M. E. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.05.032 · Cited by 75 · see citing works
Discovery and structure–activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor
Abdi, M. H., Beswick, P., Billinton, A., Chambers, L. J., Charlton, A., Collins, S. D., Collis, K. L., Dean, D. K., Fonfría, E., Gleave, R. J., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.07.033 · Cited by 74 · see citing works
A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis
Gu, B. J., Field, J., Dutertre, S., Ou, A., Kilpatrick, T. J., Lechner‐Scott, J., Scott, R. J., Lea, R. A., Taylor, B. V., Stankovich, J. M., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv278 · Cited by 73 · see citing works
Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432
Lord, B., Aluisio, L. E., Shoblock, J. R., Neff, R. A., Varlinskaya, E. I., Ceusters, M., Lovenberg, T. W., Carruthers, N. I., Bonaventure, P., Letavic, M. A., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.218487 · Cited by 73 · see citing works
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Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain
Biber, K. P. H., & Boddeke, E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00210 · Cited by 72 · see citing works
Self-citation
Direct labelling of the human P2X7receptor and identification of positive and negative cooperativity of binding
Michel, A. D., Chambers, L. J., Clay, W. C., et al. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707196 · Cited by 70 · see citing works
Clemastine Confers Neuroprotection and Induces an Anti-Inflammatory Phenotype in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis
Apolloni, S., Fabbrizio, P., Parisi, C., Amadio, S., & Volonté, C. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-9019-8 · Cited by 70 · see citing works
Negative and positive allosteric modulators of the P2X 7 receptor
Michel, A. D., Chambers, L. J., & WALTER, D. S. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707625 · Cited by 69 · see citing works
Silencing of the P2X7 receptor enhances amyloid-β phagocytosis by microglia
Ni, J., Wang, P., Zhang, J., Chen, W., & Gu, L. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.03.079 · Cited by 68 · see citing works
P2X7 Antagonists as Potential Therapeutic Agents for the Treatment of CNS Disorders
Chrovian, C. C., Rech, J. C., Bhattacharya, A., & Letavic, M. A. (2014) · Progress in medicinal chemistry · doi:10.1016/b978-0-444-63380-4.00002-0 · Cited by 67 · see citing works
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Motor neuron dysfunction in a mouse model of ALS: Gender-dependent effect of P2X7 antagonism
Cervetto, C., Frattaroli, D., Maura, G., & Marcoli, M. (2013) · Toxicology · doi:10.1016/j.tox.2013.04.004 · Cited by 66 · see citing works
Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine
Gubert, C., Fries, G. R., Pfaffenseller, B., Ferrari, P., Coutinho‐Silva, R., Morrone, F. B., Kapczinski, F. P., & Battastini, A. M. O. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-9031-z · Cited by 64 · see citing works
Mechanism of action of species‐selective P2X7receptor antagonists
Michel, A. D., Ng, S., Roman, S. A., Clay, W. C., Dean, D. K., & Walter, D. S. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00135.x · Cited by 63 · see citing works
A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334
Lord, B., Ameriks, M. K., Wang, Q., Fourgeaud, L., Vliegen, M., Verluyten, W. L. M., Haspeslagh, P., Carruthers, N. I., Lovenberg, T. W., Bonaventure, P., et al. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.09.026 · Cited by 55 · see citing works
Self-citation
P2X receptors as targets for the treatment of status epilepticus
Henshall, D. C., Dı́az-Hernández, M., Miras‐Portugal, M. T., & Engel, T. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00237 · Cited by 54 · see citing works
Synergistic Actions of Microglia and Astrocytes in the Progression of Alzheimer's Disease
Bouvier, D. S., & Murai, K. K. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-143156 · Cited by 51 · see citing works
Non-Synonymous Single Nucleotide Polymorphisms in the P2X Receptor Genes: Association with Diseases, Impact on Receptor Functions and Potential Use as Diagnosis Biomarkers
Caseley, E. A., Muench, S. P., Roger, S., Mao, H., Baldwin, S. A., & Jiang, L. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms150813344 · Cited by 51 · see citing works
Synthesis and Pharmacological Characterization of Two Novel, Brain Penetrating P2X7 Antagonists
Letavic, M. A., Lord, B., Bischoff, F., Hawryluk, N. A., Pieters, S., Rech, J. C., Sales, Z. S., Velter, A. I., Ao, H., Bonaventure, P., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml400040v · Cited by 51 · see citing works
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Involvement of the P2X7 Purinergic Receptor in Inflammation: An Update of Antagonists Series Since 2009 and their Promising Therapeutic Potential
Baudelet, D., Lipka, E., Millet, R., & Ghinet, A. (2015) · Current Medicinal Chemistry · doi:10.2174/0929867322666141212120926 · Cited by 51 · see citing works
Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists
Savall, B. M., Wu, D., Angelis, M. D., Carruthers, N. I., Ao, H., Wang, Q., Lord, B., Bhattacharya, A., & Letavic, M. A. (2015) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5b00089 · Cited by 50 · see citing works
Self-citation
ATP Receptors of Microglia Involved in Pain
Inoue, K. (2006) · Novartis Foundation symposium · doi:10.1002/9780470032244.ch21 · Cited by 49 · see citing works
The P2 Receptor Antagonist PPADS Supports Recovery from Experimental Stroke In Vivo
Lämmer, A., Beck, A., Grummich, B., Förschler, A., Krügel, T., Kahn, T., Schneider, D., Illés, P., Franke, H., & Krügel, U. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019983 · Cited by 49 · see citing works
Lack of Association of P2RX7 Gene rs2230912 Polymorphism with Mood Disorders: A Meta-Analysis
Feng, W.-P., Zhang, B., Li, W., & Liu, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088575 · Cited by 48 · see citing works
Up‐regulation of P2X7 receptor–mediated inhibition of <scp>GABA</scp> uptake by nerve terminals of the human epileptic neocortex
Barros‐Barbosa, A. R., Fonseca, A. L., Guerra‐Gomes, S., Ferreirinha, F., Santos, A., Rangel, R., Lobo, M. G., Correia‐de‐Sá, P., & Cordeiro, J. M. (2016) · Epilepsia · doi:10.1111/epi.13263 · Cited by 48 · see citing works
Receptor localization, native tissue binding and ex vivo occupancy for centrally penetrant P2X7 antagonists in the rat
Able, S., Fish, R., Bye, H., Booth, L. A., Logan, Y. R., Nathaniel, C., Hayter, P. M., & KATUGAMPOLA, S. D. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01025.x · Cited by 47 · see citing works
Possible protective role of the 489C>T P2X7R polymorphism in Alzheimer's disease
Sanz, J. M., Falzoni, S., Rizzo, R., et al. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.10.009 · Cited by 46 · see citing works
P2X purinoceptors as a link between hyperexcitability and neuroinflammation in status epilepticus
Henshall, D. C., & Engel, T. (2015) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2015.02.031 · Cited by 45 · see citing works
The role of glutamate release mediated by extrasynaptic P2X7 receptors in animal models of neuropathic pain
Andó, R. D., & Sperlágh, B. (2012) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2012.09.016 · Cited by 44 · see citing works
Medicinal Chemistry of P2X Receptors: Allosteric Modulators
Müller, C. E. (2015) · Current Medicinal Chemistry · doi:10.2174/0929867322666141210155610 · Cited by 44 · see citing works
The phenothiazine-class antipsychotic drugs prochlorperazine and trifluoperazine are potent allosteric modulators of the human P2X7 receptor
Hempel, C., Nörenberg, W., Sobottka, H., Urban, N. D., Nicke, A., Fischer, W., & Schaefer, M. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.027 · Cited by 39 · see citing works
Discovery of 2-chloro-N-((4,4-difluoro-1-hydroxycyclohexyl)methyl)-5-(5-fluoropyrimidin-2-yl)benzamide as a potent and CNS penetrable P2X7 receptor antagonist
Chen, X., Pierce, B. S., Naing, W., Grapperhaus, M. L., & Phillion, D. P. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.03.094 · Cited by 39 · see citing works
Extracellular ATP differentially affects epileptiform activity via purinergic P2X7 and adenosine A1 receptors in naive and chronic epileptic rats
Klaft, Z., Schulz, S., Maslarova, A., et al. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03724.x · Cited by 35 · see citing works
Peripheral mechanisms underlying the essential role of P2X7 receptors in the development of inflammatory hyperalgesia
Teixeira, J. M., Oliveira, M. C. G., Parada, C. A., & Tambeli, C. H. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.06.061 · Cited by 33 · see citing works
Anti-Prion Activity of Brilliant Blue G
Iwamaru, Y., Takenouchi, T., Murayama, Y., Okada, H., Imamura, M., Shimizu, Y., Hashimoto, M., Mohri, S., Yokoyama, T., & Kitani, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037896 · Cited by 32 · see citing works
Purinergic P2X7 Receptors Mediate Cell Death in Mouse Cerebellar Astrocytes in Culture
Salas, E., Carrasquero, L. M. G., Olivos-Oré, L. A., Bustillo, D., Artalejo, A. R., Miras‐Portugal, M. T., & Delicado, E. G. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.209452 · Cited by 32 · see citing works
Cloning and pharmacological characterization of the guinea pig P2X7receptor orthologue
Fonfría, E., Clay, W. C., Levy, D. S., Goodwin, J. A., Roman, S. A., Smith, G. D., Condreay, J. P., & Michel, A. D. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707596 · Cited by 31 · see citing works
Cloning and pharmacological characterization of the dog P2X7 receptor
Roman, S. A., Cusdin, F., Fonfría, E., Goodwin, J. A., Reeves, J. J., Lappin, S. C., Chambers, L. J., WALTER, D. S., Clay, W., & Michel, A. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00425.x · Cited by 30 · see citing works
Pharmacological properties of the rhesus macaque monkey P2X7 receptor
Bradley, H., Browne, L. E., Yang, W., & Jiang, L. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01399.x · Cited by 29 · see citing works
Structure–activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor
Beswick, P., Billinton, A., Chambers, L. J., Dean, D. K., Fonfría, E., Gleave, R. J., Medhurst, S. J., Michel, A. D., Moses, A. P., Patel, S., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.05.107 · Cited by 27 · see citing works
Effects of genetic variation in the P2RX7 gene on pharmacodynamics of a P2X7 receptor antagonist: a prospective genotyping approach
McHugh, S. M., Roman, S. A., Davis, B. G., Koch, A., Pickett, A. M., Richardson, J. C., Miller, S. R., Wetten, S., Cox, C. J., Karpe, F., et al. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04200.x · Cited by 23 · see citing works
The Physiology, Pharmacology and Future of P2X7 as An Analgesic Drug Target: Hype or Promise?
Bhattacharya, A., Neff, R. A., & Wickenden, A. D. (2011) · Current Pharmaceutical Biotechnology · doi:10.2174/138920111798357429 · Cited by 20 · see citing works
Self-citation
P2X7 receptor antagonist activity of the anti-allergic agent oxatomide
Yoshida, K., Ito, M., & Matsuoka, I. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.10.002 · Cited by 16 · see citing works

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Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration
Shao, F., Wang, X., Wu, H., Wu, Q., & Zhang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.825086 · Cited by 250 · see citing works
The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression
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Authors: Bhattacharya, A., & Biber, K.
Affiliations: Janssen Research & Development (United States) (US)
University Medical Center Groningen (NL)
Corresponding author: Bhattacharya, Anindya
ORCID: Bhattacharya, Anindya
Biber, Knut
Venue: Glia
Publisher: Wiley
Published: 2016-05-24
Volume: 64
Issue: 10
Pages: 1772-1787
ISSN: 0894-1491 (ISSN-L)
1098-1136
DOI: 10.1002/glia.23001
OpenAlex: W2402724338
Cited by: 221
References: 145
Citations by year: 2026: 11 · 2025: 17 · 2024: 32 · 2023: 13 · 2022: 20 · 2021: 21 · 2020: 27 · 2019: 18 · 2018: 30 · 2017: 25 · 2016: 5
FWCI: 2.57
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Glia (publishedVersion)
PubMed (publishedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Keywords: P2X7 receptor, microglia, ATP-gated ion channels, CNS drug targets, P2X7 antagonists, brain penetration, neuroinflammation, neurological disorders, mental illness, drug development
MeSH terms: Animals, Central Nervous System Diseases, Humans, Microglia, Receptors, Purinergic P2X7, Purinergic Agents

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The microglial ATP‐gated ion channel P2X7 as a CNS drug target

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