Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates

Pendergast, William; Yerxa, Benjamin R.; Douglass, James G.; Shaver, Sammy R.; Dougherty, R. W.; Redick, Catherine C.; Sims, Ingrid F; Rideout, Janet L.

doi:10.1016/s0960-894x(00)00612-0

Cited by 116 publications

(123 citation statements)

References 17 publications

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“…Furthermore, Ap 4 A is a good agonist at P2Y 2 and P2Y 4 receptors, and although Ap 3 A and Ap 5 A can also activate these receptors, they do so with less affinity. Finally, Up 4 U exhibits comparable potency with UTP as an agonist for P2Y 2 and P2Y 4 receptors, being inactive at P2Y 1 (Pendergast et al, 2001). P2Y receptors act via a G q/11 protein coupling to activate PLC␤, IP 3 formation, and mobilization of [Ca 2ϩ ] i , although coupling to adenylyl cyclase, PLA 2 , PKC, NO synthase, or BK Ca channels activation has also been described (Ralevic and Burnstock, 1998).…”

Section: Discussionmentioning

confidence: 99%

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap 4 A) and pentaphosphate (Ap 5 A) in the AH. Topic application of Ap 4 A to the cornea decreased IOP, whereas Ap 5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap n As; n ϭ 3-5) and Up 4 U (P 1 ,P 4 -(diuridine 5Ј)-tetraphosphate; INS365) in outflow facility were tested. P2Y 1 , P2Y 2 , and P2Y 4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap 3 A, Ap 4 A, and Ap 5 A induced discrete intracellular calcium concentration ([Ca 2ϩ ] i ) mobilizations compared with higher and more sustained [Ca 2ϩ ] i mobilizations after Up 4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 M Ap 3 A or Ap 4 A increased outflow facility, whereas Up 4 U or Ap 5 A did not modify it. 2-MeSADP, a selective P2Y 1 agonist, induced outflow facility increases similar to those obtained after Ap 3 A and Ap 4 A, and these were prevented by addition of the selective P2Y 1 receptor antagonist MRS-2179 (2Ј-deoxy-N 6 -methyladenosine-3Ј,5Ј-diphosphate). Our results demonstrate that the hypotensive effect of Ap 4 A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y 1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.In the eye, elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage is a major risk factor in the development of glaucoma. Glaucoma is the most important cause of irreversible nontraumatic blindness in the world and affects more than 66 million people. The main determinant of IOP is the volume of AH contained in the anterior and posterior chambers. AH is produced in the ciliary epithelium and eliminated through the outflow pathways in the anterior chamber angle. In several species, but especially in the primate eye, most AH flows through the trabecular meshwork (TM), a sponge-like filtering tissue, where it reaches Schlemm's canal and the collector channels before finally entering the venous system. The structure of the TM and its ability to modify its resistance to AH outflow play a key role in maintaining the IOP in the anterior chamber within its physiological range. TM cells express several receptors to substances released either in the AH from different ocular tissues (Mitchell et al., 1998;Coca-Prados et al., 1999) or from ocular innervation (Selbach et al., 2000) in physiologic...

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Section: Discussionmentioning

confidence: 99%

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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“…The dependence of potency at various P2Y receptors on the number of bridging phosphate units in the dinucleotide series indicates an optimum at the tetraphosphate. Newer-generation P2Y 2 receptor agonists, such as INS37217 (Up 4 dC, 52), have been reported (Pendergast et al, 2001;Yerxa et al, 2002). INS37217 is less prone to enzymatic hydrolysis than more common dinucleotide agonists.…”

Section: Atp-preferring P2ymentioning

confidence: 99%

“…ATP behaves as a competitive antagonist (Kennedy et al, 2000). Up 4 U (INS365) (Pendergast et al, 2001) and dCp 4 U (INS37217) are agonists of the human P2Y 4 receptor, whereas Ap 4 A is inactive. On the contrary, the recombinant rat and mouse P2Y 4 receptors are activated equipotently by ATP and UTP and also with a lower potency by ITP, GTP and CTP (Bogdanov et al, 1998b;Webb et al, 1998).…”

Section: P2ymentioning

confidence: 99%

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International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

et al. 2006

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“…is a stable analog of diuridine 5Ј-triphosphate, a selective agonist at the P2Y6 receptor (28). The selectivity of INS48823 has been assessed previously based on calcium mobilization in 1321N1 astrocytoma cell lines infected with a retrovirus encoding different P2Y receptors.…”

Section: Characterization Of the Effects Of The P2y6-selective Agonismentioning

confidence: 99%

P2Y6 Nucleotide Receptors Activate NF-κB and Increase Survival of Osteoclasts

Korcok¹,

Raimundo

Du³

et al. 2005

Journal of Biological Chemistry

110

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Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates

Cited by 116 publications

References 17 publications

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

P2Y6 Nucleotide Receptors Activate NF-κB and Increase Survival of Osteoclasts

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