P2X7 receptor antagonists for the treatment of systemic inflammatory disorders

Gelin, Christine F.; Bhattacharya, Anindya; Letavic, Michael A.

doi:10.1016/bs.pmch.2019.11.002

Cited by 19 publications

(23 citation statements)

References 45 publications

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“…However, improved P2X7R antagonists with suitable pharmacokinetic properties are available (Rech et al, 2016, Gelin et al, 2020 and should be used instead. As for many allosteric modulators, species differences have been observed for some P2X7R antagonists.…”

Section: P2x7 Receptor Antagonistsmentioning

confidence: 99%

“…The P2X7 receptor has been the most extensively investigated subtype for drug development, and numerous potent and selective, mainly allosteric, antagonists have been reported ( Gelin, Bhattacharya, & Letavic, 2020 ). The sulfonate dye Brilliant Blue G blocks P2X7 receptors and has been used in a number of studies due to its low cost.…”

Section: Medicinal Chemistry Of P2x Receptor Ligandsmentioning

confidence: 99%

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Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Illéš

Müller

Jacobson

et al. 2020

British J Pharmacology

207

202

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The known seven mammalian receptor (R) subunits (P2X1-7) form cationic channels gated by ATP. Three subunits compose a receptor-channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1, TM2), intracellular Nand C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D-structure and gating cycle of P2XRs. The agonist binding pocket is located at the intersection of two neighboring subunits. In addition to the mammalian P2XRs their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2XR subtypes are not available, but medicinal chemistry supplied a range of subtype selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2XRs, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7).

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Section: P2x7 Receptor Antagonistsmentioning

confidence: 99%

Section: Medicinal Chemistry Of P2x Receptor Ligandsmentioning

confidence: 99%

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Illéš

Müller

Jacobson

et al. 2020

British J Pharmacology

207

202

View full text Add to dashboard Cite

show abstract

“…Inhibition of the P2X7 receptor to block its proinflammatory effects on Aβ has been questioned by some authors that found spatial memory impairment and the alteration of other behavioral parameters in P2X7 −/− mice and in animals in which P2X7 was pharmacologically inhibited. It has to be said that these results were obtained in AD animal models and, so far, no one can predict the consequences of P2X7 antagonization in the human brain [102,178,179].…”

Section: Discussionmentioning

confidence: 99%

Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Merighi

Poloni

Terrazzan

et al. 2021

Cells

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Alzheimer’s disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A2A subtype, is particularly expressed in the brain at the striatal and hippocampal levels and appears as the most promising target to counteract neurological damage and adenosine-dependent neuroinflammation. Extracellular nucleotides (ATP, ADP, UTP, UDP, etc.) are also released from the cell or are synthesized extracellularly. They activate P2X and P2Y membrane receptors, eliciting a variety of physiological but also pathological responses. Among the latter, the chronic inflammation underlying AD is mainly caused by the P2X7 receptor subtype. In this review we offer an overview of the scientific evidence linking P1 and P2 mediated purinergic signaling to AD development. We will also discuss potential strategies to exploit this knowledge for drug development.

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“…Although hundreds of benzamide analogues have been reported as P2X7 antagonists in research papers and patents, [34] and 1,2,4-triazoles have been reported as isosteres of tetrazoles several years ago, [35] information on derivatives in which the amide bond is replaced by the bioisosteric 1,2,3-triazole is scarce. [36] Given also that the use of 1,2,3-triazoles has attracted increasing research interest for the development of new therapeutic agents, [37] we replaced the amide bond of AZ1 by its bioisostere 1,2,3-triazole ring.…”

Section: Replacement Of the Amide Bond By The 123-triazole Ringmentioning

confidence: 99%

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

et al. 2020

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The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan‐1‐yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand‐based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two‐electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl‐cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2‐chloro‐N‐[1‐(3‐(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide (56) exhibiting the best potency with an IC50 value of 0.39 μM.

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P2X7 receptor antagonists for the treatment of systemic inflammatory disorders

Cited by 19 publications

References 45 publications

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Design, Synthesis, and in vitro Evaluation of P2X7 Antagonists

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