Pharmacology of INS37217 [P1-(Uridine 5′)-P4- (2′-deoxycytidine 5′)tetraphosphate, Tetrasodium Salt], a Next-Generation P2Y2 Receptor Agonist for the Treatment of Cystic Fibrosis

Yerxa, Benjamin R.; Sabater, Juan R.; Davis, C. William; Stutts, M. Jackson; Lang-Furr, M.; Picher, Maryse; Cowlen, Matthew S.; Dougherty, R. W.; Boyer, José L.; Abraham, William M.; Boucher, Richard C.

doi:10.1124/jpet.102.035485

Cited by 138 publications

(125 citation statements)

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“…The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the…”

Section: Introductionmentioning

confidence: 99%

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Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

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Recent work has identified nucleotide agonists selective for P2Y 1 , P2Y 2 and P2Y 6 receptors and nucleotide antagonists selective for P2Y 1 , P2Y 12 and P2X 1 receptors. Selective non-nucleotide antagonists have been reported for P2Y 1 , P2Y 2 , P2Y 6 , P2Y 12 , P2Y 13 , P2X 2/3 /P2X 3 and P2X 7 receptors. For example, the dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X 2/3 /P2X 3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y 1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y 1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC 50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC 50 ) of 0.4 nM at the P2Y 1 receptor, with >10 000-fold selectivity in comparison to P2Y 12 and P2Y 13 receptors. At P2Y 6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. Extracellular purine and pyrimidine nucleotides act as neurotransmitters/modulators . These ubiquitous signalling molecules modulate the function of diverse mammalian cell types and tissues under both normal and pathophysiological conditions. Receptors for extracellular nucleotides have been characterized through medicinal chemical, molecular biological, and pharmacological approaches. The eight subtypes of P2Y receptors, denoted P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 , are all seven transmembrane-spanning (7TM) receptors, which couple to G proteins. The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the

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Section: Introductionmentioning

confidence: 99%

“…These thiophosphate derivatives may be prepared using enzymatic methods (Lazarowski et al 1996). The dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and is less prone to enzymatic hydrolysis than naturally-occurring dinucleotide agonists (Yerxa et al 2002).…”

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confidence: 99%

Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

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confidence: 99%

“…Moreover, P2Y 2 receptor activation increases mucous secretion and ciliary beat frequency (19). Thus, activation of the P2Y 2 receptor facilitates mucociliary clearance and is an important therapeutic target for treatment of cystic fibrosis and other diseases of epithelia (20).We have recently demonstrated by confocal microscopy that the P2Y 2 receptor is targeted to the apical membrane in epithelial cells of multiple lineages (21), and this localization is consistent with pharmacological studies of the receptor in epithelial cell lines (22,23). Proteins are targeted to a particular membrane surface because they contain a signal within their primary sequence that is recognized by the cell.…”

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confidence: 99%

The Apical Targeting Signal of the P2Y2 Receptor Is Located in Its First Extracellular Loop

Wolff

Nicholas

2005

Journal of Biological Chemistry

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P2Y 2 and P2Y 4 receptors, which have 52% sequence identity, are both expressed at the apical membrane of Madin-Darby canine kidney cells, but the locations of their apical targeting signals are distinctly different. The targeting signal of the P2Y 2 receptor is located between the N terminus and 7TM, whereas that of the P2Y 4 receptor is present in its C-terminal tail. To identify the apical targeting signal in the P2Y 2 receptor, regions of the P2Y 2 receptor were progressively substituted with the corresponding regions of the P2Y 4 receptor lacking its targeting signal. Characterization of these chimeras and subsequent mutational analysis revealed that four amino acids (Arg 95 , Gly 96 , Asp 97 , and Leu 108 ) in the first extracellular loop play a major role in apical targeting of the P2Y 2 receptor. Mutation of RGD to RGE had no effect on P2Y 2 receptor targeting, indicating that receptor-integrin interactions are not involved in apical targeting. P2Y 2 receptor mutants were localized in a similar manner in Caco-2 colon epithelial cells. This is the first identification of an extracellular protein-based targeting signal in a seven-transmembrane receptor.Extracellular nucleotides play an important role in a broad range of physiological and pathophysiological processes through two classes of receptors, the ligand-gated P2X receptors and the G protein-coupled P2Y receptors (1, 2). To date, pharmacological characterization and molecular cloning have identified seven P2X receptors (P2X 1-7 ) and eight P2Y receptor subtypes (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 , and P2Y 14 ). The P2Y receptors can be divided into two main subfamilies based on sequence identity and phylogenetic considerations: the P2Y 1 receptor subfamily, which is comprised of P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 receptors, and the P2Y 12 receptor subfamily, comprising P2Y 12 , P2Y 13 , and P2Y 14 receptors. The P2Y 1 receptor subfamily is coupled to activation of phospholipase C, generation of inositol phosphates, activation of protein kinase C, and mobilization of intracellular Ca 2ϩ stores. In addition to coupling to activation of phospholipase C, the P2Y 11 receptor is also coupled to G s , thereby activating adenylyl cyclase (3-5). In contrast, the three members of the P2Y 12 receptor subfamily couple to G i/o and therefore inhibit adenylyl cyclase (6 -8).Although P2Y receptors mediate a multitude of cellular responses throughout the body, one of their main functions is to regulate ion transport in polarized epithelial cells. Proteins in polarized epithelial cells can be expressed predominantly at either the apical or basolateral membrane surface, or they can be indiscriminatingly distributed to both membranes. The proper targeting of proteins to their respective membrane surface is critical in host defense, nutrient absorption, ion transport, and signal transduction. However, the mechanism(s) by which epithelial cells target proteins to a particular membrane surface remains a critical question in epithelial cell b...

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“…The cornea is a chemical and mechanical barrier that stops the entry of any foreign body, included drugs, to the anterior chamber (Leong and Tong, 2015). The corneal epithelium is the layer with a stronger barrier function (Gobbels et al, 1990;McNamara et al, 1997;Yokoi and Kinoshita, 1995), meanwhile the stroma and endothelium give less resistance to transcorneal permeability (Huang et al, 1983(Huang et al, , 1989.…”

Section: Effect On Epithelial Permeabilitymentioning

confidence: 99%

The role of dinucleoside polyphosphates on the ocular surface and other eye structures

Carracedo

Crooke

Guzmán-Aránguez

et al. 2016

Progress in Retinal and Eye Research

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a b s t r a c tDinucleoside polyphosphates comprises a group of dinucleotides formed by two nucleosides linked by a variable number of phosphates, abbreviated NpnN (where n represents the number of phosphates). These compounds are naturally occurring substances present in tears, aqueous humour and in the retina. As the consequence of their presence, these dinucleotides contribute to many ocular physiological processes. On the ocular surface, dinucleoside polyphosphates can stimulate tear secretion, mucin release from goblet cells and they help epithelial wound healing by accelerating cell migration rate. These dinucleotides can also stimulate the presence of proteins known to protect the ocular surface against microorganisms, such as lysozyme and lactoferrin. One of the latest discoveries is the ability of some dinucleotides to facilitate the paracellular way on the cornea, therefore allowing the delivery of compounds, such as antiglaucomatous ones, more easily within the eye. The compound Ap 4 A has been described being abnormally elevated in patient's tears suffering of dry eye, Sjogren syndrome, congenital aniridia, or after refractive surgery, suggesting this molecule as biomarker for dry eye condition. At the intraocular level, some diadenosine polyphosphates are abnormally elevated in glaucoma patients, and this can be related to the stimulation of a P2Y 2 receptor that increases the chloride efflux and water movement in the ciliary epithelium. In the retina, the dinucleotide dCp 4 U, has been proven to be useful to help in the recovery of retinal detachments. Altogether, dinucleoside polyphosphates are a group of compounds which present relevant physiological actions but which also can perform promising therapeutic benefits.

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Pharmacology of INS37217 [P¹-(Uridine 5′)-P⁴- (2′-deoxycytidine 5′)tetraphosphate, Tetrasodium Salt], a Next-Generation P2Y₂ Receptor Agonist for the Treatment of Cystic Fibrosis

Cited by 138 publications

References 29 publications

Agonists and Antagonists for P2 Receptors

Agonists and Antagonists for P2 Receptors

The Apical Targeting Signal of the P2Y2 Receptor Is Located in Its First Extracellular Loop

The role of dinucleoside polyphosphates on the ocular surface and other eye structures

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