Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists

Caseley, Emily A.; Muench, Stephen P.; Fishwick, Colin W. G.; Jiang, Lin‐Hua

doi:10.1016/j.bcp.2016.07.020

Cited by 23 publications

(30 citation statements)

References 45 publications

(70 reference statements)

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“…Another recent study shows that the purified panda P2X7 receptor, upon reconstitution into liposomes, forms a lipid-composition dependent dye-permeable pore that is independent of its unique C-terminal tail but facilitated by palmitoylated cysteine residues near the pore-lining helix (Karasawa et al, 2017). Nonetheless, recent studies have discovered compounds that preferentially inhibit the large pore formation without effect on the ion channel function (Caseley et al, 2016;Fowler et al, 2014). Furthermore, there is evidence to indicate an important role of the P2X7 receptor, particularly its large pore formation, in inflammatory diseases such as chronic pain (Sorge et al, 2012) and aged-related macular degeneration (Fowler et al, 2014).…”

Section: The Properties Of P2x7 Receptormentioning

confidence: 99%

“…It may be worth mentioning that a number of compounds that are potent at the rodent P2X7 receptor do not present the same activity for the human P2X7 receptor. The recent breakthroughs in the structural biology of P2X receptors are expected to accelerate the progress of discovering new P2X7 antagonists (Ahmadi and Shahlaei, 2015;Caseley et al, 2016;Fantoni et al, 2017) and provide the molecular mechanism of antagonism (Barniol-Xicota et al, 2017;Caseley et al, 2015;Karasawa and Kawate, 2016). Below we will highlight the CNS-penetrable P2X7 antagonists, focusing on the studies that explores their potential uses as a PET tracer and/or an antidepressant.…”

Section: Development Of Cns-penetrable P2x7 Antagonistsmentioning

confidence: 99%

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ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Wei

Mortadza

Yan

et al. 2018

Neuroscience & Biobehavioral Reviews

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Mood disorders are a group of psychiatric conditions that represent leading global disease burdens. Increasing evidence from clinical and preclinical studies supports that innate immune system dysfunction plays an important part in the pathophysiology of mood disorders. P2X7 receptor, belonging to the ligand-gated ion channel P2X subfamily of purinergic P2 receptors for extracellular ATP, is highly expressed in immune cells including microglia in the central nervous system (CNS) and has a vital role in mediating innate immune response. The P2X7 receptor is also important in neuron-glia signalling in the CNS. The gene encoding human P2X7 receptor is located in a locus of susceptibility to mood disorders. In this review, we will discuss the recent progress in understanding the role of the P2X7 receptor in the pathogenesis and development of mood disorders and in discovering CNS-penetrable P2X7 antagonists for potential uses in in vivo imaging to monitor brain inflammation and antidepressant therapeutics.

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Section: The Properties Of P2x7 Receptormentioning

confidence: 99%

Section: Development Of Cns-penetrable P2x7 Antagonistsmentioning

confidence: 99%

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

Wei

Mortadza

Yan

et al. 2018

Neuroscience & Biobehavioral Reviews

Self Cite

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“…These impressive achievements, along with their enabling of the interpretation of a large body of prior mutagenesis data (reviewed in Chataigneau et al, 2013 ; Jiang et al, 2013 ; Alves et al, 2014 ; Samways et al, 2014 ; Grimes and Young, 2015 ; Habermacher et al, 2016 ; Kawate, 2017 ), have led to significant breakthroughs in our understanding of channel architecture, ligand binding, and the mechanisms of channel opening, desensitization and both orthosteric and allosteric antagonism. In addition, the availability of structural data has allowed for the construction and testing of molecular models of those human receptors which still lack direct high-resolution structural data (Alves et al, 2014 ; Ahmadi et al, 2015 ; Caseley et al, 2015 , 2016 ; Farmer et al, 2015 ; Fryatt et al, 2016 ), paving the way for mutational analysis to elucidate antagonist binding sites (Farmer et al, 2015 ; Allsopp et al, 2017 ), and structure-aided drug design (Ahmadi et al, 2015 ; Caseley et al, 2015 , 2016 ).…”

Section: Introductionmentioning

confidence: 99%

The Molecular Determinants of Small-Molecule Ligand Binding at P2X Receptors

2018

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P2X receptors are trimeric eukaryotic ATP-gated cation channels. Extracellular ATP—their physiological ligand—is released as a neurotransmitter and in conditions of cell damage such as inflammation, and substantial evidence implicates P2X receptors in diseases including neuropathic pain, cancer, and arthritis. In 2009, the first P2X crystal structure, Danio rerio P2X4 in the apo- state, was published, and this was followed in 2012 by the ATP-bound structure. These structures transformed our understanding of the conformational changes induced by ATP binding and the mechanism of ligand specificity, and enabled homology modeling of mammalian P2X receptors for ligand docking and rational design of receptor modulators. P2X receptors are attractive drug targets, and a wide array of potent, subtype-selective modulators (mostly antagonists) have been developed. In 2016, crystal structures of human P2X3 in complex with the competitive antagonists TNP-ATP and A-317491, and Ailuropoda melanoleuca P2X7 in complex with a series of allosteric antagonists were published, giving fascinating insights into the mechanism of channel antagonism. In this article we not only summarize current understanding of small-molecule modulator binding at P2X receptors, but also use this information in combination with previously published structure-function data and molecular docking experiments, to hypothesize a role for the dorsal fin loop region in differential ATP potency, and describe novel, testable binding conformations for both the semi-selective synthetic P2X7 agonist 2′-(3′)-O-(4-benzoyl)benzoyl ATP (BzATP), and the P2X4-selective positive allosteric modulator ivermectin. We find that the distal benzoyl group of BzATP lies in close proximity to Lys-127, a residue previously implicated in BzATP binding to P2X7, potentially explaining the increased potency of BzATP at rat P2X7 receptors. We also present molecular docking of ivermectin to rat P2X4 receptors, illustrating a plausible binding conformation between the first and second transmembrane domains which not only tallies with previous mutagenesis studies, but would also likely have the effect of stabilizing the open channel structure, consistent with the mode of action of this positive allosteric modulator. From our docking simulations and analysis of sequence homology we propose a series of mutations likely to confer ivermectin sensitivity to human P2X1.

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“…The P2 receptor family is comprised of ligand-gated ion channel P2X receptors and G-protein coupled P2Y receptors ( 43 ). Autocrine release of ATP by glial cells activates P2X 7 receptors and may amplify pain signals through a cascade reaction ( 44 – 47 ). Thus, inhibiting P2X 7 receptors may relieve inflammatory and chronic neuropathic pain ( 37 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Long non‑coding RNA BC168687 small interfering RNA reduces high glucose and high free fatty acid‑induced expression of P2X7 receptors in satellite glial cells

Liu

Deng

et al. 2018

Mol Med Report

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Purinergic signaling contributes to inflammatory and immune responses. The activation of the P2X purinoceptor 7 (P2X7) in satellite glial cells (SGCs) may be an essential component in the promotion of inflammation and neuropathic pain. Long non-coding RNAs (lncRNAs) are involved in multiple physiological and pathological processes. The aim of the present study was to investigate the effects of a small interfering RNA for the lncRNA BC168687 on SGC P2X7 expression in a high glucose and high free fatty acids (HGHF) environment. It was demonstrated that BC168687 small interfering (si)RNA downregulated the co-expression of the P2X7 and glial fibrillary acidic protein and P2X7 mRNA expression. Additionally, HGHF may activate the mitogen-activated protein kinase signaling pathway by increasing the release of nitric oxide and reactive oxygen species in SGCs. Taken together, these results indicate that silencing BC168687 expression may downregulate the increased expression of P2X7 receptors in SGCs induced by a HGHF environment.

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Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists

Abstract: Graphical abstract

Cited by 23 publications

References 45 publications

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics

The Molecular Determinants of Small-Molecule Ligand Binding at P2X Receptors

Long non‑coding RNA BC168687 small interfering RNA reduces high glucose and high free fatty acid‑induced expression of P2X7 receptors in satellite glial cells

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