Synthesis of Extended Uridine Phosphonates Derived from an Allosteric P2Y2 Receptor Ligand

Song, Lijun; Risseeuw, Martijn; Karalić, Izet; Barrett, Matthew O.; Brown, Kyle A.; Harden, T. Kendall; Calenbergh, Serge Van

doi:10.3390/molecules19044313

Cited by 5 publications

(1 citation statement)

References 17 publications

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“…Specific inhibitors of P2Y2 are expected to be useful as new drugs for antimetastatic therapy in the context of various tumors [7]. The lack of selectivity of most currently developed P2Y2 receptor agonists indicates that they interact with P2Y2 receptors while activating other P2Y receptors, such as P2Y4 receptors and P2Y6 receptors [8,9]. Therefore, screening for P2Y2 receptor-specific modulators is particularly important.…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Cell Model for Dynamic Monitoring of Intracellular Calcium Concentration and High-Throughput Screening of P2Y2 Regulators

Liu

et al. 2022

Molecules

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P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. The P2Y2 receptor subtype is expressed in a variety of cell types and plays an important role in physiological and pathophysiological processes such as inflammatory responses and neuropathic pain. Based on this, the P2Y2 has been identified as an important drug target. The specificity of current P2Y2 receptor modulators is relatively poor, and currently, specific and efficient P2Y2 receptor modulators and efficient screening strategies are lacking. In this study, a cell model based on calcium-activated chloride channels (CaCCs) was established that can detect changes in intracellular calcium concentrations and can be used to high-throughput screen for P2Y2 receptor-specific regulators. This screening strategy is suitable for screening of most G-protein-coupled receptor regulators that mediate increases in intracellular calcium signals. The cell model consists of three components that include the endogenously expressed P2Y2 receptor protein, the exogenously expressed calcium-activated chloride channel Anoctamin-1 (Ano1), and a yellow fluorescent protein mutant expressed within the cell that is highly sensitive to iodine ions. This model will allow for high-throughput screening of GPCR regulators that mediate increased intracellular calcium signaling using the calcium-activated transport of iodide ions by Ano1. We verified the ability of the model to detect intracellular calcium ion concentration using fluorescence quenching kinetic experiments by applying existing P2Y2 agonists and inhibitors to validate the screening function of the model, and we also evaluated the performance of the model in the context of high-throughput screening studies. The experimental results revealed that the model could sensitively detect intracellular calcium ion concentration changes and that the model was accurate in regard to detecting P2Y2 modulators. The resultant value of the Z-factor was 0.69, thus indicating that the model possesses good sensitivity and specificity.

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Section: Introductionmentioning

confidence: 99%

Establishment of a Cell Model for Dynamic Monitoring of Intracellular Calcium Concentration and High-Throughput Screening of P2Y2 Regulators

Liu

et al. 2022

Molecules

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Tools and drugs for uracil nucleotide-activated P2Y receptors

Rafehi

Müller

2018

Pharmacology & Therapeutics

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Photoredox-Catalyzed Deformylative 1,4-Addition of 2′-Deoxy-5′-O-phthalimidonucleosides for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates

et al. 2018

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A concise approach for the synthesis of the 5'-carba analogs of nucleoside 5'-phosphates from 2'-deoxy-5'- O-phthalimidonucleosides by a visible-light-mediated deformylative 1,4-addition was developed. This method enabled rapid and facile generation of 4'-carbon radicals of nucleosides. Moreover, this synthetic strategy was applicable to the 5'-carba analogs of nucleoside 5'-phosphates as well as other 5'-carba nucleosides bearing methoxycarbonyl, cyano, and N-methylsulfamoyl groups.

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Synthesis of Extended Uridine Phosphonates Derived from an Allosteric P2Y2 Receptor Ligand

Cited by 5 publications

References 17 publications

Establishment of a Cell Model for Dynamic Monitoring of Intracellular Calcium Concentration and High-Throughput Screening of P2Y2 Regulators

Establishment of a Cell Model for Dynamic Monitoring of Intracellular Calcium Concentration and High-Throughput Screening of P2Y2 Regulators

Tools and drugs for uracil nucleotide-activated P2Y receptors

Photoredox-Catalyzed Deformylative 1,4-Addition of 2′-Deoxy-5′-O-phthalimidonucleosides for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates

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