5-OMe-uridine-5′-O-(α-boranodiphosphate), a novel nucleotide derivative highly active at the human P2Y6 receptor protects against death-receptor mediated glial apoptosis

Haas, Michael; Ginsburg-Shmuel, Tamar; Fischer, Bilha; Reiser, Georg

doi:10.1016/j.neulet.2014.06.030

Cited by 10 publications

(7 citation statements)

References 23 publications

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“…the south (S) conformation over the north (N) (Maruoka et al, 2010). Substitution of the uracil 5 position, e.g., with iodo or methoxy, is tolerated at P2Y 6 , but not P2Y 2 and P2Y 4 receptors (Haas et al, 2014). Thiocarbonyl substitution of the uracil 2 or 4 position is variably tolerated at the P2Y 2 , P2Y 4 , and P2Y 14 receptors.…”

Section: Medicinal Chemistry Of P2yrs: Focus On Nucleotidesmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y 2 and P2Y 11 ), ADP (P2Y 1 , P2Y 12 , and P2Y 13 ), UTP (P2Y 2 and P2Y 4 ), UDP (P2Y 6 and P2Y 14 ), and UDP glucose (P2Y 14 ). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G i -coupled P2Y 12 R and two of the G q -coupled P2Y 1 Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 12 Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.

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Section: Medicinal Chemistry Of P2yrs: Focus On Nucleotidesmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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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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“…There has been much recent progress in the design of selective P2YR ligands [42,54–60] . For example, BMS and Pfizer have reported diaryl urea derivatives as potent and selective nonnucleotide antagonists of the P2Y 1 R, a target for new antithrombotic drugs [58,59] .…”

Section: Novel P2y Receptor Ligandsmentioning

confidence: 99%

“…Most of the P2YR agonists are still labile phosphate derivatives. Fischer et al have demonstrated that introduction of a boranophosphate at the α-phosphate position of P2YR agonists greatly enhances the in vivo stability [60] . Other methods of increasing the stability of phosphate groups with varying success include methylenephosphonate bridges and thiophosphates.…”

Section: Novel P2y Receptor Ligandsmentioning

confidence: 99%

John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

Gao

Paoletta

Kiselev

et al. 2015

Computational and Structural Biotechnology Journal

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We establish structure activity relationships of extracellular nucleosides and nucleotides at G protein-coupled receptors (GPCRs), e.g. adenosine receptors (ARs) and P2Y receptors (P2YRs), respectively. We synthesize selective agents for use as pharmacological probes and potential therapeutic agents (e.g. A3AR agonists for neuropathic pain). Detailed structural information derived from the X-ray crystallographic structures within these families enables the design of novel ligands, guides modification of known agonists and antagonists, and helps predict polypharmacology. Structures were recently reported for the P2Y12 receptor (P2Y12R), an anti-thrombotic target. Comparison of agonist-bound and antagonist-bound P2Y12R indicates unprecedented structural plasticity in the outer portions of the transmembrane (TM) domains and the extracellular loops. Nonphosphate-containing ligands of the P2YRs, such as the selective P2Y14R antagonist PPTN, are desired for bioavailability and increased stability. Also, A2AAR structures are effectively applied to homology modeling of closely related A1AR and A3AR, which are not yet crystallized. Conformational constraint of normally flexible ribose with bicyclic analogues increased the ligand selectivity. Comparison of rigid A3AR agonist congeners allows the exploration of interaction of specific regions of the nucleoside analogues with the target and off-target GPCRs, such as biogenic amine receptors. Molecular modeling predicts plasticity of the A3AR at TM2 to accommodate highly rigidified ligands. Novel fluorescent derivatives of high affinity GPCR ligands are useful tool compounds for characterization of receptors and their oligomeric assemblies. Fluorescent probes are useful for characterization of GPCRs in living cells by flow cytometry and other methods. Thus, 3D knowledge of receptor binding and activation facilitates drug discovery.

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5-OMe-uridine-5′-O-(α-boranodiphosphate), a novel nucleotide derivative highly active at the human P2Y6 receptor protects against death-receptor mediated glial apoptosis

Cited by 10 publications

References 23 publications

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Ocular Purine Receptors as Drug Targets in the Eye

John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors

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