UDP made a highly promising stable, potent, and selective P2Y6-receptor agonist upon introduction of a boranophosphate moiety

Ginsburg-Shmuel, Tamar; Haas, Michael; Grbic, Djordje; Arguin, Guillaume; Nadel, Yael; Gendron, Fernand‐Pierre; Reiser, Georg; Fischer, Bilha

doi:10.1016/j.bmc.2012.07.042

Cited by 26 publications

(18 citation statements)

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“…[106][107][108] Topically applied UDP 64 reduced rabbit IOP by a maximal 17% compared to control, corresponding to an EC 50 value of 27 nM. A potent agonist of the P2Y 6 R, TG46 (67, not to be confused with the JAK2 inhibitor TG-46), was administered topically to reduce IOP in rabbits by 45%.…”

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confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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“…5-OMe-UDP and 5-F-UDP scaffolds, which are a selective P2Y 6 -R agonist / partial agonist, respectively, 8,31 or 5-alkyl/aryl-UDP scaffold, where C5-substituent is expected to improve the fit of the ligand to P2Y 6 -R hydrophobic pocket. 8,32 Specifically, UDP analogues 6-11 were obtained from nucleosides 32 and 33.…”

Section: Synthesis Of Potential P2y 6 -R Antagonistsmentioning

confidence: 99%

Synthesis and structure–activity relationship of uracil nucleotide derivatives towards the identification of human P2Y 6 receptor antagonists

Meltzer

Ethan

Arguin

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Activation of the P2Y 6 R lowers intraocular pressure; thus, such agonists are of interest for treating glaucoma. 112 P2Y 6 R is also a target for neurodegeneration; the P2Y 6 R occurs in microglial cells, where it serves as a stimulus to induce phagocytosis. 113 The P2Y 14 R receptor was found to facilitate the release of histamine from mast cells and its genetic knockout increased insulin sensitivity in target tissue.…”

Section: New Directions For Cns and Peripheral Actions Of Improvedmentioning

confidence: 99%

Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates

Jacobson

2013

J. Med. Chem.

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Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/tides are associated with new directions for therapeutics. The X-ray structures of the A 2A AR complexes with agonists and antagonists are examined in relationship to the G protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies, now is explainable from the A 2A AR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g. molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for CNS and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e. P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles.

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UDP made a highly promising stable, potent, and selective P2Y6-receptor agonist upon introduction of a boranophosphate moiety

Cited by 26 publications

References 58 publications

Ocular Purine Receptors as Drug Targets in the Eye

Ocular Purine Receptors as Drug Targets in the Eye

Synthesis and structure–activity relationship of uracil nucleotide derivatives towards the identification of human P2Y 6 receptor antagonists

Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates

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