Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders

被引：90

作者：

Bhattacharya, Anindya ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Neurosci Therapeut Area, San Diego, CA 92121 USA

来源：

FRONTIERS IN PHARMACOLOGY | 2018年 / 9卷

关键词：

P2X7; microglia; depression; IL-1beta; schizophrenia; bipolar disorder; neuroinflammation; neuropsychiatry; MAJOR DEPRESSIVE DISORDER; GATED ION-CHANNEL; P2X(7) RECEPTOR ANTAGONIST; P2RX7; GENE; PRECLINICAL EVALUATION; PSYCHIATRIC-DISORDERS; RHEUMATOID-ARTHRITIS; BIPOLAR DISORDER; MOOD DISORDERS; KNOCKOUT MICE;

D O I：

10.3389/fphar.2018.00030

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and in vivo effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for in vivo target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942) and finally, discovery of P2X7 PET ligands. This review is an attempt to bring together the current understanding of P2X7 in the CNS with a focus on P2X7 as a drug target in neuropsychiatric disorders.

引用

页数：7

共 74 条

[1] Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor [J].

Abdi, Muna H. ;

Beswick, Paul J. ;

Billinton, Andy ;

Chambers, Laura J. ;

Charlton, Andrew ;

Collins, Sue D. ;

Collis, Katharine L. ;

Dean, David K. ;

Fonfria, Elena ;

Gleave, Robert J. ;

Lejeune, Clarisse L. ;

Livermore, David G. ;

Medhurst, Stephen J. ;

Michel, Anton D. ;

Moses, Andrew P. ;

Page, Lee ;

Patel, Sadhana ;

Roman, Shilina A. ;

Senger, Stefan ;

Slingsby, Brian ;

Steadman, Jon G. A. ;

Stevens, Alexander J. ;

Walter, Daryl S. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (17) :5080-5084

[2] Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects [J].

Ali, Zahid ;

Laurijssens, Bart ;

Ostenfeld, Thor ;

McHugh, Simon ;

Stylianou, Anastasia ;

Scott-Stevens, Paul ;

Hosking, Louise ;

Dewit, Odile ;

Richardson, Jill C. ;

Chen, Chao .

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2013, 75 (01) :197-207

[3]

[Anonymous], P CINP THEM M STRESS

[4] P2RX7: Expression Responds to Sleep Deprivation and Associates with Rapid Cycling in Bipolar Disorder Type 1 [J].

Backlund, Lena ;

Lavebratt, Catharina ;

Frisen, Louise ;

Nikamo, Pernilla ;

Sudic, Dzana Hukic ;

Traskman-Bendz, Lil ;

Landen, Mikael ;

Edman, Gunnar ;

Vawter, Marquis P. ;

Osby, Urban ;

Schalling, Martin .

PLOS ONE, 2012, 7 (08)

[5] Cognitive manic symptoms associated with the P2RX7 gene in bipolar disorder [J].

Backlund, Lena ;

Nikamo, Pernilla ;

Hukic, Dzana Sudic ;

Ek, Inger Romer ;

Traskman-Bendz, Lil ;

Landen, Mikael ;

Edman, Gunnar ;

Schalling, Martin ;

Frisen, Louise ;

Osby, Urban .

BIPOLAR DISORDERS, 2011, 13 (5-6) :500-508

[6] Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder [J].

Barden, Nicholas ;

Harvey, Mario ;

Gagne, Bernard ;

Shink, Eric ;

Tremblay, Monique ;

Raymond, Catherine ;

Labbe, Michel ;

Villeneuve, Andre ;

Rochette, Denis ;

Bordeleau, Lise ;

Stadler, Herbert ;

Holsboer, Florian ;

Mueller-Myhsok, Bertram .

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2006, 141B (04) :374-382

[7] The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease [J].

Bartlett, Rachael ;

Stokes, Leanne ;

Sluyter, Ronald .

PHARMACOLOGICAL REVIEWS, 2014, 66 (03) :638-675

[8] Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: Relevance for neuropsychiatric disorders [J].

Basso, Ana M. ;

Bratcher, Natalie A. ;

Harris, Richard R. ;

Jarvis, Michael F. ;

Decker, Michael W. ;

Rueter, Lynne E. .

BEHAVIOURAL BRAIN RESEARCH, 2009, 198 (01) :83-90

[9] Structure-activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor [J].