Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists

Patberg, Marius; Isaak, Andreas; Füsser, Friederike; Zacarı́as, Natalia V. Ortiz; Vinnenberg, Laura; Schulte, Janine; Michetti, Lucia; Grey, Lucie; Horst, Cas van der; Hundehege, Petra; Koch, Oliver; Heitman, Laura H.; Budde, Thomas; Junker, Anna

doi:10.1016/j.ejmech.2021.113838

Cited by 9 publications

(2 citation statements)

References 33 publications

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“…The potent P2X7R agonist 3′- O -(4-Benzoyl)benzoyl ATP activates the human P2X7R, stably transfected in HEK293 cells. After channel opening, the dye enters the cell and binds to nucleic acids, giving a fluorescent signal. , Among the nine hit compounds, only 10 and 49 demonstrated P2X7R antagonistic activity. Since those compounds were structurally consisting of a tertiary amino group, we tested other compounds with dialkylaminoalkyl and heteroaryl groups.…”

Section: Resultsmentioning

confidence: 99%

“…The most potent group was found to be piperazine derivatives linked to substituted phenyl rings with a propanamide chain, and the target profiling studies revealed that this group of compounds solely binds to σ 1 R (Figure C). In addition, piperazines flanked by two hydrophobic (aromatic) residues are also known to fit into the P2X7R pharmacophore . In this regard, the scaffold of benzothiazole core ring attached to various piperazines with a propanamide linker was designed for the development of novel ChEI-based MTDLs that possess symptomatologic effects along with neuroprotective and DMT effects by binding to the key receptors involved for the treatment of AD (Figure D).…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

et al. 2022

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Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer’s disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo. Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

et al. 2022

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Piperazine‐based P2X4 receptor antagonists

Erlitz,

Siutkina,

Prinz

et al. 2024

Archiv der Pharmazie

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The P2X4 receptor (P2X4R), a ligand‐gated ion channel activated by ATP, plays a critical role in neuroinflammation, chronic pain, and cancer progression, making it a promising therapeutic target. In this study, we explored the design and synthesis of piperazine‐based P2X4R antagonists, building on the structural framework of paroxetine. A series of over 35 compounds were synthesized to investigate structure–activity relationships (SARs) in a Ca²⁺‐flux assay for P2X4R antagonistic activity. Several compounds outperformed paroxetine in terms of antagonistic P2X4R potency. Further studies on absorption, distribution, metabolism, excretion properties revealed that increased lipophilicity often correlated with high plasma protein binding and decreased metabolic stability, particularly in compounds with a naphthalene‐2‐yloxy group. Although promising SARs were observed, further optimization is needed to enhance antagonistic P2X4R receptor activity. This work provides important insights into the development of piperazine‐based P2X4R antagonists and lays the foundation for future therapeutic advancements targeting P2X4R‐related diseases.

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An Investigation on Linker Modifications of Cyanoguanidine‐Based P2X7 Receptor Antagonists

Garrett,

Gilchrist,

McKenzie

et al. 2024

ChemMedChem

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Despite their acknowledged significance in the inflammatory signalling cascade across a range of disease states, P2X7R antagonists have not yet proven to be effective in clinical trials. In this study, we present findings on P2X7 receptor antagonists that are based on a core adamantyl‐cyanoguanidine‐quinoline lead. To investigate the specific features of the cyanoguanidine moiety that influence compound potency we carried out a structure‐activity relationship (SAR) study. Compound potency was assessed using an in vitro dye‐uptake assay measuring P2X7R pore formation. While none of the compounds displayed superior potency to the lead, we established key structural requirements for potent P2X7R antagonism. An additional SAR using different aryl groups was performed based on the promising activity displayed by the squaramide derivative.

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Piperazine squaric acid diamides, a novel class of allosteric P2X7 receptor antagonists

Cited by 9 publications

References 33 publications

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer’s Disease

Piperazine‐based P2X4 receptor antagonists

An Investigation on Linker Modifications of Cyanoguanidine‐Based P2X7 Receptor Antagonists

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