Identification of novel selective P2Y6 receptor antagonists by high-throughput screening assay

Life Sciences
Masaaki ItoIsao Matsuoka

Abstract

The P2Y6 nucleotide receptor is widely involved in inflammatory responses, and is a promising molecular target for the treatment of inflammatory diseases. Although several P2Y6 receptor antagonists have been developed and evaluated thus far, none has successfully been developed into a therapeutic drug. In this study, we explored new promising compounds that inhibit the human P2Y6 receptor. High-throughput screening (HTS) was used to study the effects of various compounds on human P2Y6 receptors expressed in 1321N1 human astrocytoma cells by monitoring intracellular Ca(2+) concentration ([Ca(2+)]i) levels using an FDSS7000 real-time fluorescence detector. IL-8 concentration was measured by enzyme-linked immunosorbent assay. Among structurally diverse chemical libraries totalling 141,700 compounds, 43 compounds with an inhibitory activity against the P2Y6 receptor were identified. Further studies using a dose-response assay, receptor selectivity assay, and chemokine measurement assay revealed the selective P2Y6 receptor inhibitor TIM-38, which inhibited UDP-induced [Ca(2+)]i elevation in a dose-dependent manner. TIM-38 had an IC50 value of 4.3μM and inhibited P2Y6 without affecting the response induced by four other human P2Y or ...Continue Reading

Citations

Jan 13, 2018·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Najam A Sharif
Feb 10, 2018·MedChemComm·Kiran S TotiKenneth A Jacobson
Mar 19, 2020·Pain·Kenneth A JacobsonDaniela Salvemini
Jun 17, 2020·Molecular Imaging·Hamideh Zarrinmayeh, Paul R Territo
Dec 12, 2018·Journal of Medicinal Food·Natiele Carla da Silva FerreiraLuiz Anastacio Alves
Apr 9, 2021·Bioorganic & Medicinal Chemistry Letters·Young-Hwan JungKenneth A Jacobson

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