Structure-Activity Relationships and Therapeutic Potential of Purinergic P2X7 Receptor Antagonists


Citar

Texto integral

Resumo

The purinergic P2X7 receptor (P2X7R), an ATP-gated non-selective cation channel, has emerged as a gatekeeper of inflammation that controls the release of proinflammatory cytokines. As a key player in initiating the inflammatory signaling cascade, the P2X7 receptor is currently under intense scrutiny as a target for the treatment of different pathologies, including chronic inflammatory disorders (rheumatoid arthritis and osteoarthritis), chronic neuropathic pain, mood disorders (depression and anxiety), neurodegenerative diseases, ischemia, cancer (leukemia), and many others. For these reasons, pharmaceutical companies have invested in discovering compounds able to modulate the P2X7R and filed many patent applications. This review article presents an account of P2X7R structure, function, and tissue distribution, emphasizing its role in inflammation. Next, we illustrate the different chemical classes of non-competitive P2X7R antagonists reported by highlighting their properties and qualities as clinical candidates for treating inflammatory disorders and neurodegenerative diseases. We also discuss the efforts to develop effective Positron Emission Tomography (PET) radioligands to progress the understanding of the pathomechanisms of neurodegenerative disorders, to provide evidence of drug-target engagement, and to assist clinical dose selection for novel drug therapies.

Sobre autores

Imane Ghafir El Idrissi

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

Sabina Podlewska

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences

Email: info@benthamscience.net

Carmen Abate

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

Andrzej Bojarski

Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences

Email: info@benthamscience.net

Enza Lacivita

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Autor responsável pela correspondência
Email: info@benthamscience.net

Marcello Leopoldo

Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro

Email: info@benthamscience.net

Bibliografia

  1. North, R.A. Molecular physiology of P2X receptors. Physiol. Rev., 2002, 82(4), 1013-1067. doi: 10.1152/physrev.00015.2002 PMID: 12270951
  2. Burnstock, G.; Kennedy, C. Is there a basis for distinguishing two types of P2-purinoceptor? Gen. Pharmacol., 1985, 16(5), 433-440. doi: 10.1016/0306-3623(85)90001-1 PMID: 2996968
  3. Mehta, N.; Kaur, M.; Singh, M.; Chand, S.; Vyas, B.; Silakari, P.; Bahia, M.S.; Silakari, O. Purinergic receptor P2X7: A novel target for anti-inflammatory therapy. Bioorg. Med. Chem., 2014, 22(1), 54-88. doi: 10.1016/j.bmc.2013.10.054 PMID: 24314880
  4. Syed, N.H.; Kennedy, C. Pharmacology of P2X receptors. WIREs Membr. Transp. Signal, 2012, 1, 16-30.
  5. Oliveira-Giacomelli, Á.; Petiz, L.L.; Andrejew, R.; Turrini, N.; Silva, J.B.; Sack, U.; Ulrich, H. Role of P2X7 receptors in immune responses during neurodegeneration. Front. Cell. Neurosci., 2021, 15, 662935. doi: 10.3389/fncel.2021.662935 PMID: 34122013
  6. Junger, W.G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol., 2011, 11(3), 201-212. doi: 10.1038/nri2938 PMID: 21331080
  7. Soto, F.; Garcia-Guzman, M.; Stühmer, W. Cloned ligand-gated channels activated by extracellular ATP (P2X receptors). J. Membr. Biol., 1997, 160(2), 91-100. doi: 10.1007/s002329900298 PMID: 9354701
  8. Coddou, C.; Yan, Z.; Obsil, T.; Huidobro-Toro, J.P.; Stojilkovic, S.S. Activation and regulation of purinergic P2X receptor channels. Pharmacol. Rev., 2011, 63(3), 641-683. doi: 10.1124/pr.110.003129 PMID: 21737531
  9. Sluyter, R. The P2X7 receptor. Adv. Exp. Med. Biol., 2017, 1051, 17-53. doi: 10.1007/5584_2017_59 PMID: 28676924
  10. Di Virgilio, F.; Dal Ben, D.; Sarti, A.C.; Giuliani, A.L.; Falzoni, S. The P2X7 receptor in infection and inflammation. Immunity, 2017, 47(1), 15-31. doi: 10.1016/j.immuni.2017.06.020 PMID: 28723547
  11. Jiang, L.H.; Baldwin, J.M.; Roger, S.; Baldwin, S.A. Insights into the molecular mechanisms underlying mammalian P2X7 receptor functions and contributions in diseases, revealed by structural modeling and single nucleotide polymorphisms. Front. Pharmacol., 2013, 4, 55. doi: 10.3389/fphar.2013.00055 PMID: 23675347
  12. Roger, S.; Mei, Z.Z.; Baldwin, J.M.; Dong, L.; Bradley, H.; Baldwin, S.A.; Surprenant, A.; Jiang, L.H. Single nucleotide polymorphisms that were identified in affective mood disorders affect ATP-activated P2X7 receptor functions. J. Psychiatr. Res., 2010, 44(6), 347-355. doi: 10.1016/j.jpsychires.2009.10.005 PMID: 19931869
  13. Fuller, S.J.; Stokes, L.; Skarratt, K.K.; Gu, B.J.; Wiley, J.S. Genetics of the P2X7 receptor and human disease. Purinergic Signal., 2009, 5(2), 257-262. doi: 10.1007/s11302-009-9136-4 PMID: 19319666
  14. Sperlágh, B.; Vizi, E.; Wirkner, K.; Illes, P. P2X7 receptors in the nervous system. Prog. Neurobiol., 2006, 78(6), 327-346. doi: 10.1016/j.pneurobio.2006.03.007 PMID: 16697102
  15. Lenertz, L.Y.; Gavala, M.L.; Zhu, Y.; Bertics, P.J. Transcriptional control mechanisms associated with the nucleotide receptor P2X7, a critical regulator of immunologic, osteogenic, and neurologic functions. Immunol. Res., 2011, 50(1), 22-38. doi: 10.1007/s12026-011-8203-4 PMID: 21298493
  16. Wiley, J.S.; Sluyter, R.; Gu, B.J.; Stokes, L.; Fuller, S.J. The human P2X7 receptor and its role in innate immunity. Tissue Antigens, 2011, 78(5), 321-332. doi: 10.1111/j.1399-0039.2011.01780.x
  17. Torres, G.E.; Egan, T.M.; Voigt, M.M. Hetero-oligomeric assembly of P2X receptor subunits. Specificities exist with regard to possible partners. J. Biol. Chem., 1999, 274(10), 6653-6659. doi: 10.1074/jbc.274.10.6653 PMID: 10037762
  18. Nicke, A. Homotrimeric complexes are the dominant assembly state of native P2X7 subunits. Biochem. Biophys. Res. Commun., 2008, 377(3), 803-808. doi: 10.1016/j.bbrc.2008.10.042 PMID: 18938136
  19. Kawate, T.; Michel, J.C.; Birdsong, W.T.; Gouaux, E. Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature, 2009, 460(7255), 592-598. doi: 10.1038/nature08198 PMID: 19641588
  20. Habermacher, C.; Dunning, K.; Chataigneau, T.; Grutter, T. Molecular structure and function of P2X receptors. Neuropharmacology, 2016, 104, 18-30. doi: 10.1016/j.neuropharm.2015.07.032 PMID: 26231831
  21. McCarthy, A.E.; Yoshioka, C.; Mansoor, S.E. Full-Length P2X7 structures reveal how palmitoylation prevents channel desensitization. Cell, 2019, 179(3), 659-670.e13. doi: 10.1016/j.cell.2019.09.017 PMID: 31587896
  22. Costa-Junior, H.M.; Marques-da-Silva, C.; Vieira, F.S.; Monção-Ribeiro, L.C.; Coutinho-Silva, R. Lipid metabolism modulation by the P2X7 receptor in the immune system and during the course of infection: new insights into the old view. Purinergic Signal., 2011, 7(4), 381-392. doi: 10.1007/s11302-011-9255-6 PMID: 21845440
  23. Bidula, S.M.; Cromer, B.A.; Walpole, S.; Angulo, J.; Stokes, L. Mapping a novel positive allosteric modulator binding site in the central vestibule region of human P2X7. Sci. Rep., 2019, 9(1), 3231. doi: 10.1038/s41598-019-39771-5 PMID: 30824738
  24. Bin Dayel, A.; Evans, R.J.; 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, 96(3), 355-363. doi: 10.1124/mol.119.116715 PMID: 31263019
  25. Caseley, E.A.; Muench, S.P.; Baldwin, S.A.; Simmons, K.; Fishwick, C.W.; Jiang, L.H. Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human. Bioorg. Med. Chem. Lett., 2015, 25(16), 3164-3167. doi: 10.1016/j.bmcl.2015.06.001 PMID: 26099538
  26. Karasawa, A.; Kawate, T. Structural basis for subtype-specific inhibition of the P2X7 receptor. eLife, 2016, 5, e22153. doi: 10.7554/eLife.22153 PMID: 27935479
  27. Surprenant, A.; Rassendren, F.; Kawashima, E.; North, R.A.; Buell, G. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science, 1996, 272(5262), 735-738. doi: 10.1126/science.272.5262.735 PMID: 8614837
  28. Wilhelm, K.; Ganesan, J.; Müller, T.; Dürr, C.; Grimm, M.; Beilhack, A.; Krempl, C.D.; Sorichter, S.; Gerlach, U.V.; Jüttner, E.; Zerweck, A.; Gärtner, F.; Pellegatti, P.; Di Virgilio, F.; Ferrari, D.; Kambham, N.; Fisch, P.; Finke, J.; Idzko, M.; Zeiser, R. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat. Med., 2010, 16(12), 1434-1438. doi: 10.1038/nm.2242 PMID: 21102458
  29. Khakh, B.S.; Alan North, R. P2X receptors as cell-surface ATP sensors in health and disease. Nature, 2006, 442(7102), 527-532. doi: 10.1038/nature04886 PMID: 16885977
  30. Pellegatti, P.; Raffaghello, L.; Bianchi, G.; Piccardi, F.; Pistoia, V.; Di Virgilio, F. Increased level of extracellular ATP at tumor sites: In vivo imaging with plasma membrane luciferase. PLoS One, 2008, 3(7), e2599. doi: 10.1371/journal.pone.0002599 PMID: 18612415
  31. Eltzschig, H.K.; Sitkovsky, M.V.; Robson, S.C. Purinergic signaling during inflammation. N. Engl. J. Med., 2012, 367(24), 2322-2333. doi: 10.1056/NEJMra1205750 PMID: 23234515
  32. Rassendren, F.; Buell, G.N.; Virginio, C.; Collo, G.; North, R.A.; Surprenant, A. The permeabilizing ATP receptor, P2X7. Cloning and expression of a human cDNA. J. Biol. Chem., 1997, 272(9), 5482-5486. doi: 10.1074/jbc.272.9.5482 PMID: 9038151
  33. Chessell, I.P.; Simon, J.; Hibell, A.D.; Michel, A.D.; Barnard, E.A.; Humphrey, P.P.A. Cloning and functional characterisation of the mouse P2X 7 receptor. FEBS Lett., 1998, 439(1-2), 26-30. doi: 10.1016/S0014-5793(98)01332-5 PMID: 9849870
  34. Adinolfi, E.; Giuliani, A.L.; De Marchi, E.; Pegoraro, A.; Orioli, E.; Di Virgilio, F. The P2X7 receptor: A main player in inflammation. Biochem. Pharmacol., 2018, 151, 234-244. doi: 10.1016/j.bcp.2017.12.021 PMID: 29288626
  35. Di Virgilio, F. Purinergic signalling in the immune system. A brief update. Purinergic Signal., 2007, 3(1-2), 1-3. doi: 10.1007/s11302-006-9048-5 PMID: 18404413
  36. Jacob, F.; Novo, C.P.; Bachert, C.; Van Crombruggen, K. Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses. Purinergic Signal., 2013, 9(3), 285-306. doi: 10.1007/s11302-013-9357-4 PMID: 23404828
  37. Peng, K.; Liu, L.; Wei, D.; Lv, Y.; Wang, G.; Xiong, W.; Wang, X.; Altaf, A.; Wang, L.; He, D.; Wang, H.; Qu, P. P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int. J. Mol. Med., 2015, 35(5), 1179-1188. doi: 10.3892/ijmm.2015.2129 PMID: 25761252
  38. Lister, M.F.; Sharkey, J.; Sawatzky, D.A.; Hodgkiss, J.P.; Davidson, D.J.; Rossi, A.G.; Finlayson, K. The role of the purinergic P2X7 receptor in inflammation. J. Inflamm. , 2007, 4(1), 5. doi: 10.1186/1476-9255-4-5 PMID: 17367517
  39. Lenertz, L.Y.; Gavala, M.L.; Hill, L.M.; Bertics, P.J. Cell signaling via the P2X7 nucleotide receptor: Linkage to ROS production, gene transcription, and receptor trafficking. Purinergic Signal., 2009, 5(2), 175-187. doi: 10.1007/s11302-009-9133-7 PMID: 19263245
  40. Apolloni, S.; Parisi, C.; Pesaresi, M.G.; Rossi, S.; Carrì, M.T.; Cozzolino, M.; Volonté, C.; D’Ambrosi, N. The NADPH oxidase pathway is dysregulated by the P2X7 receptor in the SOD1-G93A microglia model of amyotrophic lateral sclerosis. J. Immunol., 2013, 190(10), 5187-5195. doi: 10.4049/jimmunol.1203262 PMID: 23589615
  41. Wang, B.; Sluyter, R. P2X7 receptor activation induces reactive oxygen species formation in erythroid cells. Purinergic Signal., 2013, 9(1), 101-112. doi: 10.1007/s11302-012-9335-2 PMID: 23014887
  42. Gross, O.; Thomas, C.J.; Guarda, G.; Tschopp, J. The inflammasome: An integrated view. Immunol. Rev., 2011, 243(1), 136-151. doi: 10.1111/j.1600-065X.2011.01046.x PMID: 21884173
  43. Tschopp, J. Mitochondria: Sovereign of inflammation? Eur. J. Immunol., 2011, 41(5), 1196-1202. doi: 10.1002/eji.201141436 PMID: 21469137
  44. Hung, S.C.; Choi, C.H.; Said-Sadier, N.; Johnson, L.; Atanasova, K.R.; Sellami, H.; Yilmaz, Ö.; Ojcius, D.M. P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation. PLoS One, 2013, 8(7), e70210. doi: 10.1371/journal.pone.0070210 PMID: 23936165
  45. Minkiewicz, J.; de Rivero Vaccari, J.P.; Keane, R.W. Human astrocytes express a novel NLRP2 inflammasome. Glia, 2013, 61(7), 1113-1121. doi: 10.1002/glia.22499 PMID: 23625868
  46. Sanz, J.M.; Chiozzi, P.; Ferrari, D.; Colaianna, M.; Idzko, M.; Falzoni, S.; Fellin, R.; Trabace, L.; Di Virgilio, F. Activation of microglia by amyloid beta requires P2X7 receptor expression. J. Immunol., 2009, 182(7), 4378-4385. doi: 10.4049/jimmunol.0803612 PMID: 19299738
  47. Sáez-Orellana, F.; Fuentes-Fuentes, M.C.; Godoy, P.A.; Silva-Grecchi, T.; Panes, J.D.; Guzmán, L.; Yévenes, G.E.; Gavilán, J.; Egan, T.M.; Aguayo, L.G.; Fuentealba, J. P2X receptor overexpression induced by soluble oligomers of amyloid beta peptide potentiates synaptic failure and neuronal dyshomeostasis in cellular models of Alzheimer’s disease. Neuropharmacology, 2018, 128, 366-378. doi: 10.1016/j.neuropharm.2017.10.027 PMID: 29079292
  48. Parvathenani, L.K.; Tertyshnikova, S.; Greco, C.R.; Roberts, S.B.; Robertson, B.; Posmantur, R. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer’s disease. J. Biol. Chem., 2003, 278(15), 13309-13317. doi: 10.1074/jbc.M209478200 PMID: 12551918
  49. McLarnon, J.G.; Ryu, J.K.; Walker, D.G.; Choi, H.B. Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J. Neuropathol. Exp. Neurol., 2006, 65(11), 1090-1097. doi: 10.1097/01.jnen.0000240470.97295.d3 PMID: 17086106
  50. Ryu, J.K.; McLarnon, J.G. Block of purinergic P2X7 receptor is neuroprotective in an animal model of Alzheimer’s disease. Neuroreport, 2008, 19(17), 1715-1719. doi: 10.1097/WNR.0b013e3283179333 PMID: 18852683
  51. Durrenberger, P.F.; Grünblatt, E.; Fernando, F.S.; Monoranu, C.M.; Evans, J.; Riederer, P.; Reynolds, R.; Dexter, D.T. Inflammatory pathways in Parkinson’s disease; a BNE microarray study. Parkinsons Dis., 2012, 2012, 1-16. doi: 10.1155/2012/214714 PMID: 22548201
  52. Jiang, T.; Hoekstra, J.; Heng, X.; Kang, W.; Ding, J.; Liu, J.; Chen, S.; Zhang, J. P2X7 receptor is critical in α-synuclein–mediated microglial NADPH oxidase activation. Neurobiol. Aging, 2015, 36(7), 2304-2318. doi: 10.1016/j.neurobiolaging.2015.03.015 PMID: 25983062
  53. 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.; Andrade, G.M. 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. Neuropharmacology, 2014, 81, 142-152. doi: 10.1016/j.neuropharm.2014.01.045 PMID: 24508709
  54. Kumar, S.; Mishra, A.; Krishnamurthy, S. Purinergic antagonism prevents mitochondrial dysfunction and behavioral deficits associated with dopaminergic toxicity induced by 6-OHDA in rats. Neurochem. Res., 2017, 42(12), 3414-3430. doi: 10.1007/s11064-017-2383-9 PMID: 28836128
  55. Volonté, C.; Amadio, S.; Liguori, F.; Fabbrizio, P. Duality of P2X7 receptor in amyotrophic lateral sclerosis. Front. Pharmacol., 2020, 11, 1148. doi: 10.3389/fphar.2020.01148 PMID: 32792962
  56. Fabbrizio, P.; Apolloni, S.; Bianchi, A.; Salvatori, I.; Valle, C.; Lanzuolo, C.; Bendotti, C.; Nardo, G.; Volonté, C. P2X7 activation enhances skeletal muscle metabolism and regeneration in SOD1G93A mouse model of amyotrophic lateral sclerosis. Brain Pathol., 2020, 30(2), 272-282. doi: 10.1111/bpa.12774 PMID: 31376190
  57. Yiangou, Y.; Facer, P.; Durrenberger, P.; Chessell, I.P.; Naylor, A.; Bountra, C.; Banati, R.R.; Anand, P. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol., 2006, 6(1), 12. doi: 10.1186/1471-2377-6-12 PMID: 16512913
  58. Nukui, T.; Matsui, A.; Niimi, H.; Sugimoto, T.; Hayashi, T.; Dougu, N.; Konishi, H.; Yamamoto, M.; Anada, R.; Matsuda, N.; Kitajima, I.; Nakatsuji, Y. Increased cerebrospinal fluid adenosine 5′-triphosphate in patients with amyotrophic lateral sclerosis. BMC Neurol., 2021, 21(1), 255. doi: 10.1186/s12883-021-02288-4 PMID: 34193068
  59. Gandelman, M.; Peluffo, H.; Beckman, J.S.; Cassina, P.; Barbeito, L. Extracellular ATP and the P2X7receptor in astrocyte-mediated motor neuron death: Implications for amyotrophic lateral sclerosis. J. Neuroinflammation, 2010, 7(1), 33. doi: 10.1186/1742-2094-7-33 PMID: 20534165
  60. Fabbrizio, P.; Amadio, S.; Apolloni, S.; Volonté, C. P2X7 Receptor activation modulates autophagy in SOD1-G93A mouse microglia. Front. Cell. Neurosci., 2017, 11, 249. doi: 10.3389/fncel.2017.00249 PMID: 28871219
  61. Matute, C.; Torre, I.; Pérez-Cerdá, F.; Pérez-Samartín, A.; Alberdi, E.; Etxebarria, E.; Arranz, A.M.; Ravid, R.; Rodríguez-Antigüedad, A.; Sánchez-Gómez, M.; Domercq, M. P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J. Neurosci., 2007, 27(35), 9525-9533. doi: 10.1523/JNEUROSCI.0579-07.2007 PMID: 17728465
  62. Amadio, S.; Parisi, C.; Piras, E.; Fabbrizio, P.; Apolloni, S.; Montilli, C.; Luchetti, S.; Ruggieri, S.; Gasperini, C.; Laghi-Pasini, F.; Battistini, L.; Volonté, C. Modulation of P2X7 receptor during inflammation in multiple sclerosis. Front. Immunol., 2017, 8, 1529. doi: 10.3389/fimmu.2017.01529 PMID: 29187851
  63. Cai, X.; Yao, Y.; Teng, F.; Li, Y.; Wu, L.; Yan, W.; Lin, N. The role of P2X7 receptor in infection and metabolism: Based on inflammation and immunity. Int. Immunopharmacol. 2021, 101(Pt A), 108297. doi: 10.1016/j.intimp.2021.108297 PMID: 34717202
  64. Portales-Cervantes, L.; Niño-Moreno, P.; Doníz-Padilla, L.; Baranda-Candido, L.; García-Hernández, M.; Salgado-Bustamante, M.; González-Amaro, R.; Portales-Pérez, D. Expression and function of the P2X7 purinergic receptor in patients with systemic lupus erythematosus and rheumatoid arthritis. Hum. Immunol., 2010, 71(8), 818-825. doi: 10.1016/j.humimm.2010.05.008 PMID: 20493226
  65. Fan, Z.D.; Zhang, Y.Y.; Guo, Y.H.; Huang, N.; Ma, H.H.; Huang, H.; Yu, H.G. Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice. Sci. Rep., 2016, 6(1), 35804. doi: 10.1038/srep35804 PMID: 27775097
  66. McInnes, I.B.; Cruwys, S.; Bowers, K.; Braddock, M. Targeting the P2X7 receptor in rheumatoid arthritis: Biological rationale for P2X7 antagonism. Clin. Exp. Rheumatol., 2014, 32(6), 878-882. PMID: 25288220
  67. Lopez-Castejon, G.; Theaker, J.; Pelegrin, P.; Clifton, A.D.; Braddock, M.; Surprenant, A. P2X(7) receptor-mediated release of cathepsins from macrophages is a cytokine-independent mechanism potentially involved in joint diseases. J. Immunol., 2010, 185(4), 2611-2619. doi: 10.4049/jimmunol.1000436 PMID: 20639492
  68. Neves, A.R.; Castelo-Branco, M.T.L.; Figliuolo, V.R.; Bernardazzi, C.; Buongusto, F.; Yoshimoto, A.; Nanini, H.F.; Coutinho, C.M.L.M.; Carneiro, A.J.V.; Coutinho-Silva, R.; de Souza, H.S.P. Overexpression of ATP-activated P2X7 receptors in the intestinal mucosa is implicated in the pathogenesis of Crohn’s disease. Inflamm. Bowel Dis., 2014, 20(3), 444-457. doi: 10.1097/01.MIB.0000441201.10454.06 PMID: 24412990
  69. Gentile, D.; Lazzerini, P.E.; Gamberucci, A.; Natale, M.; Selvi, E.; Vanni, F.; Alì, A.; Taddeucci, P.; Del-Ry, S.; Cabiati, M.; Della-Latta, V.; Abraham, D.J.; Morales, M.A.; Fulceri, R.; Laghi-Pasini, F.; Capecchi, P.L. Searching novel therapeutic targets for scleroderma: P2X7-receptor is upregulated and promotes a fibrogenic phenotype in systemic sclerosis fibroblasts. Front. Pharmacol., 2017, 8, 638. doi: 10.3389/fphar.2017.00638 PMID: 28955239
  70. Adinolfi, E.; Callegari, M.G.; Ferrari, D.; Bolognesi, C.; Minelli, M.; Wieckowski, M.R.; Pinton, P.; Rizzuto, R.; Di Virgilio, F. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol. Biol. Cell, 2005, 16(7), 3260-3272. doi: 10.1091/mbc.e04-11-1025 PMID: 15901833
  71. Adinolfi, E.; Callegari, M.G.; Cirillo, M.; Pinton, P.; Giorgi, C.; Cavagna, D.; Rizzuto, R.; Di Virgilio, F. Expression of the P2X7 receptor increases the Ca2+ content of the endoplasmic reticulum, activates NFATc1, and protects from apoptosis. J. Biol. Chem., 2009, 284(15), 10120-10128. doi: 10.1074/jbc.M805805200 PMID: 19204004
  72. Hill, L.M.; Gavala, M.L.; Lenertz, L.Y.; Bertics, P.J. Extracellular ATP may contribute to tissue repair by rapidly stimulating purinergic receptor X7-dependent vascular endothelial growth factor release from primary human monocytes. J. Immunol., 2010, 185(5), 3028-3034. doi: 10.4049/jimmunol.1001298 PMID: 20668222
  73. Gu, B.J.; Wiley, J.S. Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor. Blood, 2006, 107(12), 4946-4953. doi: 10.1182/blood-2005-07-2994 PMID: 16514055
  74. Qian, F.; Xiao, J.; Hu, B.; Sun, N.; Yin, W.; Zhu, J. High expression of P2X7R is an independent postoperative indicator of poor prognosis in colorectal cancer. Hum. Pathol., 2017, 64, 61-68. doi: 10.1016/j.humpath.2017.03.019 PMID: 28412208
  75. Choi, J.H.; Ji, Y.G.; Ko, J.J.; Cho, H.J.; Lee, D.H. Activating P2X7 receptors increases proliferation of human pancreatic cancer cells via ERK1/2 and JNK. Pancreas, 2018, 47(5), 643-651. doi: 10.1097/MPA.0000000000001055 PMID: 29683976
  76. Qiu, Y.; Li, W.; Zhang, H.; Liu, Y.; Tian, X.X.; Fang, W.G. P2X7 mediates ATP-driven invasiveness in prostate cancer cells. PLoS One, 2014, 9(12), e114371. doi: 10.1371/journal.pone.0114371 PMID: 25486274
  77. Lara, R.; Adinolfi, E.; Harwood, C.A.; Philpott, M.; Barden, J.A.; Di Virgilio, F.; McNulty, S. P2X7 in cancer: From molecular mechanisms to therapeutics. Front. Pharmacol., 2020, 11, 793. doi: 10.3389/fphar.2020.00793 PMID: 32581786
  78. Danquah, W.; Meyer-Schwesinger, C.; Rissiek, B.; Pinto, C.; Serracant-Prat, A.; Amadi, M.; Iacenda, D.; Knop, J.H.; Hammel, A.; Bergmann, P.; Schwarz, N.; Assunção, J.; Rotthier, W.; Haag, F.; Tolosa, E.; Bannas, P.; Boué-Grabot, E.; Magnus, T.; Laeremans, T.; Stortelers, C.; Koch-Nolte, F. Nanobodies that block gating of the P2X7 ion channel ameliorate inflammation. Sci. Transl. Med., 2016, 8(366), 366ra162. doi: 10.1126/scitranslmed.aaf8463 PMID: 27881823
  79. Salvestrini, V.; Orecchioni, S.; Talarico, G.; Reggiani, F.; Mazzetti, C.; Bertolini, F.; Orioli, E.; Adinolfi, E.; Virgilio, F.D.; Pezzi, A.; Cavo, M.; Lemoli, R.M.; Curti, A. Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells. Oncotarget, 2017, 8(4), 5895-5908. doi: 10.18632/oncotarget.13927 PMID: 27980223
  80. Souza, C.O.; Santoro, G.F.; Figliuolo, V.R.; Nanini, H.F.; de Souza, H.S.P.; Castelo-Branco, M.T.L.; Abalo, A.A.; Paiva, M.M.; Coutinho, C.M.L.M.; Coutinho-Silva, R. Extracellular ATP induces cell death in human intestinal epithelial cells. Biochim. Biophys. Acta, Gen. Subj., 2012, 1820(12), 1867-1878. doi: 10.1016/j.bbagen.2012.08.013 PMID: 22951220
  81. White, N.; Butler, P.E.M.; Burnstock, G. Human melanomas express functional P2X7 receptors. Cell Tissue Res., 2005, 321(3), 411-418. doi: 10.1007/s00441-005-1149-x PMID: 15991050
  82. Tamajusuku, A.S.K.; Villodre, E.S.; Paulus, R.; Coutinho-Silva, R.; Battasstini, A.M.O.; Wink, M.R.; Lenz, G. Characterization of ATP-induced cell death in the GL261 mouse glioma. J. Cell. Biochem., 2010, 109(5), 983-991. doi: 10.1002/jcb.22478 PMID: 20069573
  83. Jiang, L.H.; Mackenzie, A.B.; North, R.A.; Surprenant, A. Brilliant blue G selectively blocks ATP-gated rat P2X(7) receptors. Mol. Pharmacol., 2000, 58(1), 82-88. doi: 10.1124/mol.58.1.82 PMID: 10860929
  84. Gargett, C.E.; Wiley, J.S. The isoquinoline derivative KN-62 a potent antagonist of the P2Z-receptor of human lymphocytes. Br. J. Pharmacol., 1997, 120(8), 1483-1490. doi: 10.1038/sj.bjp.0701081 PMID: 9113369
  85. Donnelly-Roberts, D.L.; Namovic, M.T.; Han, P.; Jarvis, M.F. Mammalian P2X7 receptor pharmacology: Comparison of recombinant mouse, rat and human P2X7 receptors. Br. J. Pharmacol., 2009, 157(7), 1203-1214. doi: 10.1111/j.1476-5381.2009.00233.x PMID: 19558545
  86. McGaraughty, S.; Chu, K.L.; Namovic, M.T.; Donnelly-Roberts, D.L.; Harris, R.R.; Zhang, X.F.; Shieh, C.C.; Wismer, C.T.; Zhu, C.Z.; Gauvin, D.M.; Fabiyi, A.C.; Honore, P.; Gregg, R.J.; Kort, M.E.; Nelson, D.W.; Carroll, W.A.; Marsh, K.; Faltynek, C.R.; Jarvis, M.F. P2X7-related modulation of pathological nociception in rats. Neuroscience, 2007, 146(4), 1817-1828. doi: 10.1016/j.neuroscience.2007.03.035 PMID: 17478048
  87. Honore, P.; Donnelly-Roberts, D.; Namovic, M.T.; Hsieh, G.; Zhu, C.Z.; Mikusa, J.P.; Hernandez, G.; Zhong, C.; Gauvin, D.M.; Chandran, P.; Harris, R.; Medrano, A.P.; Carroll, W.; Marsh, K.; Sullivan, J.P.; Faltynek, C.R.; Jarvis, M.F. A-740003 N-(1-(cyanoimino)(5-quinolinylamino) methylamino-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, 319(3), 1376-1385. doi: 10.1124/jpet.106.111559 PMID: 16982702
  88. Broom, D.C.; Matson, D.J.; Bradshaw, E.; Buck, M.E.; Meade, R.; Coombs, S.; Matchett, M.; Ford, K.K.; Yu, W.; Yuan, J.; Sun, S.H.; Ochoa, R.; Krause, J.E.; Wustrow, D.J.; Cortright, D.N. Characterization of N -(Adamantan-1-ylmethyl)-5-(3 R -aminopyrrolidin-1-yl)methyl-2-chloro-benzamide, a P2X 7 antagonist in animal models of pain and inflammation. J. Pharmacol. Exp. Ther., 2008, 327(3), 620-633. doi: 10.1124/jpet.108.141853 PMID: 18772321
  89. Gum, R.J.; Wakefield, B.; Jarvis, M.F. P2X receptor antagonists for pain management: Examination of binding and physicochemical properties. Purinergic Signal., 2012, 8(S1), 41-56. doi: 10.1007/s11302-011-9272-5 PMID: 22086553
  90. Donnelly-Roberts, D.L.; Jarvis, M.F. Discovery of P2X 7 receptor-selective antagonists offers new insights into P2X 7 receptor function and indicates a role in chronic pain states. Br. J. Pharmacol., 2007, 151(5), 571-579. doi: 10.1038/sj.bjp.0707265 PMID: 17471177
  91. Allsopp, R.C.; Dayl, S.; Schmid, R.; Evans, R.J. Unique residues in the ATP gated human P2X7 receptor define a novel allosteric binding pocket for the selective antagonist AZ10606120. Sci. Rep., 2017, 7(1), 725. doi: 10.1038/s41598-017-00732-5 PMID: 28389651
  92. Guile, S.D.; Alcaraz, L.; Birkinshaw, T.N.; Bowers, K.C.; Ebden, M.R.; Furber, M.; Stocks, M.J. Antagonists of the P2X(7) receptor. From lead identification to drug development. J. Med. Chem., 2009, 52(10), 3123-3141. doi: 10.1021/jm801528x PMID: 19191585
  93. Baxter, A.; Bent, J.; Bowers, K.; Braddock, M.; Brough, S.; Fagura, M.; Lawson, M.; McInally, T.; Mortimore, M.; Robertson, M.; Weaver, R.; Webborn, P. Hit-to-Lead studies: The discovery of potent adamantane amide P2X7 receptor antagonists. Bioorg. Med. Chem. Lett., 2003, 13(22), 4047-4050. doi: 10.1016/j.bmcl.2003.08.034 PMID: 14592505
  94. Wilkinson, S.M.; Gunosewoyo, H.; Barron, M.L.; Boucher, A.; McDonnell, M.; Turner, P.; Morrison, D.E.; Bennett, M.R.; McGregor, I.S.; Rendina, L.M.; Kassiou, M. The first CNS-active carborane: A novel P2X7 receptor antagonist with antidepressant activity. ACS Chem. Neurosci., 2014, 5(5), 335-339. doi: 10.1021/cn500054n PMID: 24689484
  95. Wilkinson, S.M.; Barron, M.L.; O’Brien-Brown, J.; Janssen, B.; Stokes, L.; Werry, E.L.; Chishty, M.; Skarratt, K.K.; Ong, J.A.; Hibbs, D.E.; Vugts, D.J.; Fuller, S.; Windhorst, A.D.; Kassiou, M. Pharmacological evaluation of novel bioisosteres of an adamantanyl benzamide P2X7 Receptor antagonist. ACS Chem. Neurosci., 2017, 8(11), 2374-2380. doi: 10.1021/acschemneuro.7b00272 PMID: 28841278
  96. Dombroski, M.A.; Duplantier, A.J.; Subramanyam, C. Benzamide inhibitors of the P2X7 receptor. PCT Appl. N. WO 2004/099146, 2004.
  97. Chen, X.; Pierce, B.; Naing, W.; Grapperhaus, M.L.; Phillion, D.P. 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. Bioorg. Med. Chem. Lett., 2010, 20(10), 3107-3111. doi: 10.1016/j.bmcl.2010.03.094 PMID: 20392639
  98. Duplantier, A.J.; Dombroski, M.A.; Subramanyam, C.; Beaulieu, A.M.; Chang, S.P.; Gabel, C.A.; Jordan, C.; Kalgutkar, A.S.; Kraus, K.G.; Labasi, J.M.; Mussari, C.; Perregaux, D.G.; Shepard, R.; Taylor, T.J.; Trevena, K.A.; Whitney-Pickett, C.; Yoon, K. 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. Bioorg. Med. Chem. Lett., 2011, 21(12), 3708-3711. doi: 10.1016/j.bmcl.2011.04.077 PMID: 21565499
  99. Subramanyam, C.; Duplantier, A.J.; Dombroski, M.A.; Chang, S.P.; Gabel, C.A.; Whitney-Pickett, C.; Perregaux, D.G.; Labasi, J.M.; Yoon, K.; Shepard, R.M.; Fisher, M. Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor. Bioorg. Med. Chem. Lett., 2011, 21(18), 5475-5479. doi: 10.1016/j.bmcl.2011.06.117 PMID: 21782426
  100. Stock, T.C.; Bloom, B.J.; Wei, N.; Ishaq, S.; Park, W.; Wang, X.; Gupta, P.; Mebus, C.A. 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, 39(4), 720-727. doi: 10.3899/jrheum.110874 PMID: 22382341
  101. Guile, S.D.; Ebden, M. Quinoline derivatives for the treatment of inflammatory diseases. PCT Appl. N. Patent: WO 2008/114002,, 2008.
  102. Guile, S.D.; Thompson, T. A quinoline derivative acting as a P2X7-receptor antagonist. PCT Appl. N. Patent: WO 2009/070116,, 2009.
  103. Xiao, Y.; Karra, S.; Goutopoulos, A.; Morse, N.T.; Zhang, S.; Dhanabal, M.; Tian, H.; Seenisamy, J.; Jayadevan, J.; Caldwell, R.; Potnick, J.; Bleich, M.; Chekler, E.; Sherer, B.; Sriraman, V. Synthesis and SAR development of quinoline analogs as novel P2X7 receptor antagonists. Bioorg. Med. Chem. Lett., 2019, 29(13), 1660-1664. doi: 10.1016/j.bmcl.2019.04.033 PMID: 31031055
  104. Letavic, M.A.; Lord, B.; Bischoff, F.; Hawryluk, N.A.; Pieters, S.; Rech, J.C.; Sales, Z.; Velter, A.I.; Ao, H.; Bonaventure, P.; Contreras, V.; Jiang, X.; Morton, K.L.; Scott, B.; Wang, Q.; Wickenden, A.D.; Carruthers, N.I.; Bhattacharya, A. Synthesis and pharmacological characterization of two novel, brain penetrating P2X7 antagonists. ACS Med. Chem. Lett., 2013, 4(4), 419-422. doi: 10.1021/ml400040v PMID: 24900687
  105. Kilburn, J.P.; Rasmussen, L.K.; Jessing, M.; Eldemenky, E.M.; Chen, B.; Jiang, Y.; Hopper, A.T. Benzamides. PCT Appl. N. Patent: WO 2014/057078, 2014.
  106. Kilburn, J.P.; Rasmussen, L.K.; Jessing, M.; Eldemenky, E.M.; Chen, B.; Jiang, Y. N N -(2-(cyclic amine)ethyl)benzamide derivatives as P2X7 inhibitors. PCT Appl. N. Patent: WO 2014/057080, , 2014.
  107. Kilburn, J.P.; Hopper, A.T.; Juhl, M. Inhibitor of the p2x7 receptor., PCT Appl. N. Patent: WO 2017/076825, 2014.
  108. Hopper, A.T.; Juhl, M.; Hornberg, J.; Badolo, L.; Kilburn, J.P.; Thougaard, A.; Smagin, G.; Song, D.; Calice, L.; Menon, V.; Dale, E.; Zhang, H.; Cajina, M.; Nattini, M.E.; Gandhi, A.; Grenon, M.; Jones, K.; Khayrullina, T.; Chandrasena, G.; Thomsen, C.; Zorn, S.H.; Brodbeck, R.; Poda, S.B.; Staal, R.; Möller, T. Synthesis and characterization of the novel rodent-active and CNS-Penetrant P2X7 receptor antagonist Lu AF27139. J. Med. Chem., 2021, 64(8), 4891-4902. doi: 10.1021/acs.jmedchem.0c02249 PMID: 33822617
  109. Love, C.J.; Leenaerts, J.E.; Cooymans, L.P.; Lebsack, A.D.; Branstetter, B.J.; Rech, J.C.; Gleason, E.A.; Venable, J.D.; Wiener, D.; Smith, D.M.; Breitenbucher, J.G. PCT Appl. N. Patent: WO 2009/132000,, 2009.
  110. Rech, J.C.; Bhattacharya, A.; Branstetter, B.J.; Love, C.J.; Leenaerts, J.E.; Cooymans, L.P.; Eckert, W.A., III; Ao, H.; Wang, Q.; Chaplan, S.R.; Wickenden, A.D.; Lebsack, A.D.; Breitenbucher, J.G. The discovery and preclinical characterization of 6-chloro- N -(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists. Bioorg. Med. Chem. Lett., 2016, 26(19), 4781-4784. doi: 10.1016/j.bmcl.2016.08.029 PMID: 27595421
  111. Dean, D.K.; Munoz-Muriedas, J.; Sime, M.; Steadman, J.G.A.; Thewlis, R.E.A.; Trani, G.; Walter, D.S. 5,6,7,8- Tetrahydro1,2,4triazolo4,3-apyrazine derivatives as P2X7 modulators. PCT Appl. N Patent: WO 2010/125102,, 2010.
  112. Rudolph, D.A.; Alcazar, J.; Ameriks, M.K.; Anton, A.B.; Ao, H.; Bonaventure, P.; Carruthers, N.I.; Chrovian, C.C.; De Angelis, M.; Lord, B.; Rech, J.C.; Wang, Q.; Bhattacharya, A.; Andres, J.I.; Letavic, M.A. Novel methyl substituted 1-(5,6-dihydro-1,2,4triazolo4,3-apyrazin-7(8H)-yl)methanones are P2X7 antagonists. Bioorg. Med. Chem. Lett., 2015, 25(16), 3157-3163. doi: 10.1016/j.bmcl.2015.06.004 PMID: 26099534
  113. Chrovian, C.C.; Soyode-Johnson, A.; Ao, H.; Bacani, G.M.; Carruthers, N.I.; Lord, B.; Nguyen, L.; Rech, J.C.; Wang, Q.; Bhattacharya, A.; Letavic, M.A. Novel phenyl-substituted 5,6-dihydro-1,2,4triazolo4,3-apyrazine P2X7 antagonists with robust target engagement in rat brain. ACS Chem. Neurosci., 2016, 7(4), 490-497. doi: 10.1021/acschemneuro.5b00303 PMID: 26752113
  114. Savall, B.M.; Wu, D.; De Angelis, M.; Carruthers, N.I.; Ao, H.; Wang, Q.; Lord, B.; Bhattacharya, A.; Letavic, M.A. Synthesis, SAR, and pharmacological characterization of brain penetrant P2X7 receptor antagonists. ACS Med. Chem. Lett., 2015, 6(6), 671-676. doi: 10.1021/acsmedchemlett.5b00089 PMID: 26101572
  115. Letavic, M.A.; Savall, B.M.; Allison, B.D.; Aluisio, L.; Andres, J.I.; De Angelis, M.; Ao, H.; Beauchamp, D.A.; Bonaventure, P.; Bryant, S.; Carruthers, N.I.; Ceusters, M.; Coe, K.J.; Dvorak, C.A.; Fraser, I.C.; Gelin, C.F.; Koudriakova, T.; Liang, J.; Lord, B.; Lovenberg, T.W.; Otieno, M.A.; Schoetens, F.; Swanson, D.M.; Wang, Q.; Wickenden, A.D.; Bhattacharya, A. 4-Methyl-6,7-dihydro-4 H -triazolo4,5- cpyridine-Based P2X7 receptor antagonists: optimization of pharmacokinetic properties leading to the identification of a clinical candidate. J. Med. Chem., 2017, 60(11), 4559-4572. doi: 10.1021/acs.jmedchem.7b00408 PMID: 28493698
  116. Swanson, D.M.; Savall, B.M.; Coe, K.J.; Schoetens, F.; Koudriakova, T.; Skaptason, J.; Wall, J.; Rech, J.; Deng, X.; De Angelis, M.; Everson, A.; Lord, B.; Wang, Q.; Ao, H.; Scott, B.; Sepassi, K.; Lovenberg, T.W.; Carruthers, N.I.; Bhattacharya, A.; Letavic, M.A. Identification of (R)-(2-Chloro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyridin-2-yl)-4-methyl-6,7-dihydro-1 H -imidazo4,5- cpyridin-5(4 H)-yl)methanone (JNJ 54166060), a small molecule antagonist of the P2X7 receptor. J. Med. Chem., 2016, 59(18), 8535-8548. doi: 10.1021/acs.jmedchem.6b00989 PMID: 27548392
  117. Ziff, J.; Rudolph, D.A.; Stenne, B.; Koudriakova, T.; Lord, B.; Bonaventure, P.; Lovenberg, T.W.; Carruthers, N.I.; Bhattacharya, A.; Letavic, M.A.; Shireman, B.T. Substituted 5,6-(Dihydropyrido3,4- dpyrimidin-7(8 H)-yl)-methanones as P2X7 antagonists. ACS Chem. Neurosci., 2016, 7(4), 498-504. doi: 10.1021/acschemneuro.5b00304 PMID: 26754558
  118. Ameriks, M.K.; Ao, H.; Carruthers, N.I.; Lord, B.; Ravula, S.; Rech, J.C.; Savall, B.M.; Wall, J.L.; Wang, Q.; Bhattacharya, A.; Letavic, M.A. Preclinical characterization of substituted 6,7-dihydro-1,2,4triazolo4,3- apyrazin-8(5 H)-one P2X7 receptor antagonists. Bioorg. Med. Chem. Lett., 2016, 26(2), 257-261. doi: 10.1016/j.bmcl.2015.12.052 PMID: 26707399
  119. Carroll, W.A.; Perez-Medrano, A.; Florjancic, A.S.; Nelson, D.W.; Peddi, S.; Li, T.; Bunnelle, E.M.; Hirst, G.C.; Li, B. Amino-tetrazoles analogues and methods of use., PCT Appl. N. Patent: WO 2005/111003, 2005.
  120. Carroll, W.A. P2X7 receptor antagonists and methods of use. . PCT Appl. N. Patent: WO2007056046, 2007.
  121. Lopez-Tapia, F.; Walker, K.A.M.; Brotherton-Pleiss, C.; Caroon, J.; Nitzan, D.; Lowrie, L.; Gleason, S.; Zhao, S.H.; Berger, J.; Cockayne, D.; Phippard, D.; Suttmann, R.; Fitch, W.L.; Bourdet, D.; Rege, P.; Huang, X.; Broadbent, S.; Dvorak, C.; Zhu, J.; Wagner, P.; Padilla, F.; Loe, B.; Jahangir, A.; Alker, A. Novel series of dihydropyridinone P2X7 receptor antagonists. J. Med. Chem., 2015, 58(21), 8413-8426. doi: 10.1021/acs.jmedchem.5b00365 PMID: 26460788
  122. Beswick, P.J.; Chambers, L.J.; Davies, D.J.; Dean, D.K.; Demont, E.H.; Susan Roomans, S.; Walter, D.S. N N (phenylmethyl)-2-(1H-pyrazol-4-yl) acetamide derivatives as P2X7 antagonists for the treatment of pain, inflammation and neurodegeneration. PCT Appl. N. Patent: WO 2007/141267,, 2007.
  123. Beswick, P.J.; Dean, D.K.; Walter, D.S. Pyrazole derivatives as P2X7 modulators.. PCT Appl. N. PCT App N. Patent: WO 2008/125600,, 2008.
  124. Chambers, L.J.; Stevens, A.J.; Moses, A.P.; Michel, A.D.; Walter, D.S.; Davies, D.J.; Livermore, D.G.; Fonfria, E.; Demont, E.H.; Vimal, M.; Theobald, P.J.; Beswick, P.J.; Gleave, R.J.; Roman, S.A.; Senger, S. Synthesis and structure–activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor. Bioorg. Med. Chem. Lett., 2010, 20(10), 3161-3164. doi: 10.1016/j.bmcl.2010.03.096 PMID: 20399651
  125. Beswick, P.J.; Billinton, A.; Chambers, L.J.; Dean, D.K.; Fonfria, E.; Gleave, R.J.; Medhurst, S.J.; Michel, A.D.; Moses, A.P.; Patel, S.; Roman, S.A.; Roomans, S.; Senger, S.; Stevens, A.J.; Walter, D.S. Structure–activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor. Bioorg. Med. Chem. Lett., 2010, 20(15), 4653-4656. doi: 10.1016/j.bmcl.2010.05.107 PMID: 20579878
  126. Gleave, R.J.; Walter, D.S.; Beswick, P.J.; Fonfria, E.; Michel, A.D.; Roman, S.A.; Tang, S.P. Synthesis and biological activity of a series of tetrasubstituted-imidazoles as P2X7 antagonists. Bioorg. Med. Chem. Lett., 2010, 20(16), 4951-4954. doi: 10.1016/j.bmcl.2010.05.018 PMID: 20634071
  127. Abdi, M.H.; Beswick, P.J.; Billinton, A.; Chambers, L.J.; Charlton, A.; Collins, S.D.; Collis, K.L.; Dean, D.K.; Fonfria, E.; Gleave, R.J.; Lejeune, C.L.; Livermore, D.G.; Medhurst, S.J.; Michel, A.D.; Moses, A.P.; Page, L.; Patel, S.; Roman, S.A.; Senger, S.; Slingsby, B.; Steadman, J.G.A.; Stevens, A.J.; Walter, D.S. Discovery and structure–activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor. Bioorg. Med. Chem. Lett., 2010, 20(17), 5080-5084. doi: 10.1016/j.bmcl.2010.07.033 PMID: 20673717
  128. Ali, Z.; Laurijssens, B.; Ostenfeld, T.; McHugh, S.; Stylianou, A.; Scott-Stevens, P.; Hosking, L.; Dewit, O.; Richardson, J.C.; Chen, C. Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects. Br. J. Clin. Pharmacol., 2013, 75(1), 197-207. doi: 10.1111/j.1365-2125.2012.04320.x PMID: 22568863
  129. Abberley, L.; Bebius, A.; Beswick, P.J.; Billinton, A.; Collis, K.L.; Dean, D.K.; Fonfria, E.; Gleave, R.J.; Medhurst, S.J.; Michel, A.D.; Moses, A.P.; Patel, S.; Roman, S.A.; Scoccitti, T.; Smith, B.; Steadman, J.G.A.; Walter, D.S. Identification of 2-oxo-N-(phenylmethyl)-4-imidazolidine-carboxamide antagonists of the P2X7 receptor. Bioorg. Med. Chem. Lett., 2010, 20(22), 6370-6374. doi: 10.1016/j.bmcl.2010.09.101 PMID: 20934331
  130. Wilson, A.W.; Medhurst, S.J.; Dixon, C.I.; Bontoft, N.C.; Winyard, L.A.; Brackenborough, K.T.; Alba, J.; Clarke, C.J.; Gunthorpe, M.J.; Hicks, G.A.; Bountra, C.; McQueen, D.S.; Chessell, I.P. An animal model of chronic inflammatory pain: Pharmacological and temporal differentiation from acute models. Eur. J. Pain, 2006, 10(6), 537-549. doi: 10.1016/j.ejpain.2005.08.003 PMID: 16199187
  131. Betschmann, P.; Carroll, W.A.; Ericsson, A.M.; Fix-Stenzel, S.R.; Friedman, M.; Hirst, G.C.; Josephsohn, N.S.; Li, B.; Perez-Medrano, A.; Morytko, M.J.; Rafferty, P.; Chen, H. Piperazines as P2X7 antagonists. PCT Appl. N. Patent: WO 2008/005368,, 2008.
  132. Morytko, M.J.; Betschmann, P.; Woller, K.; Ericsson, A.; Chen, H.; Donnelly-Roberts, D.L.; Namovic, M.T.; Jarvis, M.F.; Carroll, W.A.; Rafferty, P. Synthesis and in vitro activity of N′-cyano-4-(2-phenylacetyl)-N-o-tolylpiperazine-1-carboximidamide P2X7 antagonists. Bioorg. Med. Chem. Lett., 2008, 18(6), 2093-2096. doi: 10.1016/j.bmcl.2008.01.094 PMID: 18272365
  133. Patberg, M.; Isaak, A.; Füsser, F.; Ortiz Zacarías, N.V.; Vinnenberg, L.; Schulte, J.; Michetti, L.; Grey, L.; van der Horst, C.; Hundehege, P.; Koch, O.; Heitman, L.H.; Budde, T.; Junker, A. Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists. Eur. J. Med. Chem., 2021, 226, 113838. doi: 10.1016/j.ejmech.2021.113838 PMID: 34571173
  134. O’Brien-Brown, J.; Jackson, A.; Reekie, T.A.; Barron, M.L.; Werry, E.L.; Schiavini, P.; McDonnell, M.; Munoz, L.; Wilkinson, S.; Noll, B.; Wang, S.; Kassiou, M. Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists. Eur. J. Med. Chem., 2017, 130, 433-439. doi: 10.1016/j.ejmech.2017.02.060 PMID: 28279849
  135. Calzaferri, F.; Narros-Fernández, P.; de Pascual, R.; de Diego, A.M.G.; Nicke, A.; Egea, J.; García, A.G.; de los Ríos, C. Synthesis and pharmacological evaluation of novel non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation. J. Med. Chem., 2021, 64(4), 2272-2290. doi: 10.1021/acs.jmedchem.0c02145 PMID: 33560845
  136. Faria, R.X.; Oliveira, F.H.; Salles, J.P.; Oliveira, A.S.; von Ranke, N.L.; Bello, M.L.; Rodrigues, C.R.; Castro, H.C.; Louvis, A.R.; Martins, D.L.; Ferreira, V.F. 1,4-Naphthoquinones potently inhibiting P2X7 receptor activity. Eur. J. Med. Chem., 2018, 143, 1361-1372. doi: 10.1016/j.ejmech.2017.10.033 PMID: 29133043
  137. Pacheco, P.A.F.; Galvão, R.M.S.; Faria, A.F.M.; Von Ranke, N.; Rangel, M.S.; Ribeiro, T.M.; Bello, M.; Rodrigues, C.R.; Ferreira, V.F.; da Rocha, D.R.; Faria, R.X. 8-Hydroxy-2-(1H-1,2,3-triazol-1-yl)-1,4-naphtoquinone derivatives inhibited P2X7 Receptor-Induced dye uptake into murine macrophages. Bioorg. Med. Chem., 2019, 27(8), 1449-1455. doi: 10.1016/j.bmc.2018.11.036 PMID: 30528164
  138. Pislyagin, E.; Kozlovskiy, S.; Menchinskaya, E.; Chingizova, E.; Likhatskaya, G.; Gorpenchenko, T.; Sabutski, Y.; Polonik, S.; Aminin, D. Synthetic 1,4-Naphthoquinones inhibit P2X7 receptors in murine neuroblastoma cells. Bioorg. Med. Chem., 2021, 31, 115975. doi: 10.1016/j.bmc.2020.115975 PMID: 33401207
  139. Park, J.H.; Lee, G.E.; Lee, S.D.; Hien, T.T.; Kim, S.; Yang, J.W.; Cho, J.H.; Ko, H.; Lim, S.C.; Kim, Y.G.; Kang, K.W.; Kim, Y.C. Discovery of novel 2,5-dioxoimidazolidine-based P2X(7) receptor antagonists as constrained analogues of KN62. J. Med. Chem., 2015, 58(5), 2114-2134. doi: 10.1021/jm500324g PMID: 25597334
  140. Park, J.H.; Lee, G.E.; Lee, S.D.; Ko, H.; Kim, Y.C. Structure–activity relationship studies of pyrimidine-2,4-dione derivatives as potent P2X7 receptor antagonists. Eur. J. Med. Chem., 2015, 106, 180-193. doi: 10.1016/j.ejmech.2015.10.036 PMID: 26547056
  141. Matasi, J.J.; Brumfield, S.; Tulshian, D.; Czarnecki, M.; Greenlee, W.; Garlisi, C.G.; Qiu, H.; Devito, K.; Chen, S.C.; Sun, Y.; Bertorelli, R.; Geiss, W.; Le, V.D.; Martin, G.S.; Vellekoop, S.A.; Haber, J.; Allard, M.L. Synthesis and SAR development of novel P2X7 receptor antagonists for the treatment of pain: Part 1. Bioorg. Med. Chem. Lett., 2011, 21(12), 3805-3808. doi: 10.1016/j.bmcl.2011.04.034 PMID: 21570840
  142. Mahmood, A.; Ali Shah, S.J.; Iqbal, J. Design and synthesis of adamantane-1-carbonyl thiourea derivatives as potent and selective inhibitors of h-P2X4 and h-P2X7 receptors: An emerging therapeutic tool for treatment of inflammation and neurological disorders. Eur. J. Med. Chem., 2022, 231, 114162. doi: 10.1016/j.ejmech.2022.114162 PMID: 35123298
  143. Rudin, M.; Weissleder, R. Molecular imaging in drug discovery and development. Nat. Rev. Drug Discov., 2003, 2(2), 123-131. doi: 10.1038/nrd1007 PMID: 12563303
  144. Pike, V.W. Considerations in the development of reversibly binding PET radioligands for brain imaging. Curr. Med. Chem., 2016, 23(18), 1818-1869. doi: 10.2174/0929867323666160418114826 PMID: 27087244
  145. Janssen, B.; Vugts, D.; Windhorst, A.; Mach, R. PET imaging of microglial activation beyond targeting TSPO. Molecules, 2018, 23(3), 607. doi: 10.3390/molecules23030607 PMID: 29518005
  146. Janssen, B.; Ory, D.; Wilkinson, S.M.; Vugts, D.J.; Kooijman, E.; Verbeek, J.; Funke, U.; Molenaar, G.T.; Kruijer, P.S.; Lammertsma, A.A.; Kassiou, M.; Bormans, G.; Windhorst, A.D. Initial evaluation of P2X7R antagonists 11CA-740003 and 11CSMW64-D16 as PET tracers of microglialactivation in neuroinflammation. J. Labelled Comp. Radiopharm., 2015, 58, S277.
  147. Janssen, B.; Vugts, D.J.; Wilkinson, S.M.; Ory, D.; Chalon, S.; Hoozemans, J.J.M.; Schuit, R.C.; Beaino, W.; Kooijman, E.J.M.; van den Hoek, J.; Chishty, M.; Doméné, A.; Van der Perren, A.; Villa, A.; Maggi, A.; Molenaar, G.T.; Funke, U.; Shevchenko, R.V.; Baekelandt, V.; Bormans, G.; Lammertsma, A.A.; Kassiou, M.; Windhorst, A.D. Identification of the allosteric P2X7 receptor antagonist 11CSMW139 as a PET tracer of microglial activation. Sci. Rep., 2018, 8(1), 6580. doi: 10.1038/s41598-018-24814-0 PMID: 29700413
  148. Hagens, M.H.J.; Golla, S.S.V.; Janssen, B.; Vugts, D.J.; Beaino, W.; Windhorst, A.D.; O’Brien-Brown, J.; Kassiou, M.; Schuit, R.C.; Schwarte, L.A.; de Vries, H.E.; Killestein, J.; Barkhof, F.; van Berckel, B.N.M.; Lammertsma, A.A. The P2X7 receptor tracer 11CSMW139 as an in vivo marker of neuroinflammation in multiple sclerosis: A first-in man study. Eur. J. Nucl. Med. Mol. Imaging, 2020, 47(2), 379-389. doi: 10.1007/s00259-019-04550-x PMID: 31705174
  149. Territo, P.R.; Meyer, J.A.; Peters, J.S.; Riley, A.A.; McCarthy, B.P.; Gao, M.; Wang, M.; Green, M.A.; Zheng, Q.H.; Hutchins, G.D. Characterization of 11C-GSK1482160 for targeting the P2X7 receptor as a biomarker for neuroinflammation. J. Nucl. Med., 2017, 58(3), 458-465. doi: 10.2967/jnumed.116.181354 PMID: 27765863
  150. Han, J.; Liu, H.; Liu, C.; Jin, H.; Perlmutter, J.S.; Egan, T.M.; Tu, Z. Pharmacologic characterizations of a P2X7 receptor-specific radioligand, 11CGSK1482160 for neuroinflammatory response. Nucl. Med. Commun., 2017, 38(5), 372-382. doi: 10.1097/MNM.0000000000000660 PMID: 28338530
  151. Green, M.; Hutchins, G.; Fletcher, J.; Territo, W.; Polson, H.; Trussel, H.; Wissman, C.; Zheng, Q-H.; Gao, M.; Wang, M.; Glick-Wilson, B. Distribution of the P2X7-receptor-targeted 11CGSK1482160 radiopharmaceutical in normal human subjects. J. Nucl. Med., 2018, 59(Suppl. 1), 1009.
  152. Gao, M.; Wang, M.; Meyer, J.A.; Territo, P.R.; Hutchins, G.D.; Zarrinmayeh, H.; Zheng, Q.H. Synthesis and in vitro biological evaluation of new P2X7R radioligands 11Chalo-GSK1482160 analogs. Bioorg. Med. Chem. Lett., 2019, 29(12), 1476-1480. doi: 10.1016/j.bmcl.2019.04.018 PMID: 31005444
  153. Ory, D.; Celen, S.; Gijsbers, R.; Van Den Haute, C.; Postnov, A.; Koole, M.; Vandeputte, C.; Andrés, J.I.; Alcazar, J.; De Angelis, M.; Langlois, X.; Bhattacharya, A.; Schmidt, M.; Letavic, M.A.; Vanduffel, W.; Van Laere, K.; Verbruggen, A.; Debyser, Z.; Bormans, G. Preclinical evaluation of a P2X7 receptor-selective radiotracer: PET studies in a rat model with local overexpression of the human P2X7 receptor and in nonhuman primates. J. Nucl. Med., 2016, 57(9), 1436-1441. doi: 10.2967/jnumed.115.169995 PMID: 27199364
  154. Van Weehaeghe, D.; Koole, M.; Schmidt, M.E.; Deman, S.; Jacobs, A.H.; Souche, E.; Serdons, K.; Sunaert, S.; Bormans, G.; Vandenberghe, W.; Van Laere, K. 11CJNJ54173717, 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, 46(10), 2051-2064. doi: 10.1007/s00259-019-04369-6 PMID: 31243495
  155. Fantoni, E.R.; Dal Ben, D.; Falzoni, S.; Di Virgilio, F.; Lovestone, S.; Gee, A. Design, synthesis and evaluation in an LPS rodent model of neuroinflammation of a novel 18F-labelled PET tracer targeting P2X7. EJNMMI Res., 2017, 7(1), 31. doi: 10.1186/s13550-017-0275-2 PMID: 28374288
  156. Koole, M.; Schmidt, M.E.; Hijzen, A.; Ravenstijn, P.; Vandermeulen, C.; Van Weehaeghe, D.; Serdons, K.; Celen, S.; Bormans, G.; Ceusters, M.; Zhang, W.; Van Nueten, L.; Kolb, H.; de Hoon, J.; Van Laere, K. 18F-JNJ-64413739, a novel PET ligand for the P2X7 ion channel: Radiation dosimetry, kinetic modeling, test-retest variability, and occupancy of the P2X7 antagonist JNJ-54175446. J. Nucl. Med., 2019, 60(5), 683-690. doi: 10.2967/jnumed.118.216747 PMID: 30262518
  157. Mertens, N.; Schmidt, M.E.; Hijzen, A.; Van Weehaeghe, D.; Ravenstijn, P.; Depre, M.; de Hoon, J.; Van Laere, K.; Koole, M. Minimally invasive quantification of cerebral P2X7R occupancy using dynamic 18FJNJ-64413739 PET and MRA-driven image derived input function. Sci. Rep., 2021, 11(1), 16172. doi: 10.1038/s41598-021-95715-y PMID: 34373571
  158. Morgan, J.; Moreno, O.; Alves, M.; Baz, Z.; Menéndez Méndez, A.; Leister, H.; Melia, C.; Smith, J.; Visekruna, A.; Nicke, A.; Bhattacharya, A.; Ceusters, M.; Henshall, D.C.; Gómez-Vallejo, V.; Llop, J.; Engel, T. Increased uptake of the P2X7 receptor radiotracer18 F‐JNJ ‐64413739 in the brain and peripheral organs according to the severity of status epilepticus in male mice. Epilepsia, 2023, 64(2), 511-523. doi: 10.1111/epi.17484 PMID: 36507708
  159. Fu, Z.; Lin, Q.; Hu, B.; Zhang, Y.; Chen, W.; Zhu, J.; Zhao, Y.; Choi, H.S.; Shi, H.; Cheng, D. P2X7 PET radioligand 18F-PTTP for differentiation of lung tumor from inflammation. J. Nucl. Med., 2019, 60(7), 930-936. doi: 10.2967/jnumed.118.222547 PMID: 30655332

Arquivos suplementares

Arquivos suplementares
Ação
1. JATS XML
Baixar

Declaração de direitos autorais © Bentham Science Publishers, 2024