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A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist

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Abstract

Extracellular nucleotides can regulate the production/drainage of the aqueous humor via activation of P2 receptors, thus affecting the intraocular pressure (IOP). We evaluated 5-OMe-UDP(α-B), 1A, a potent P2Y6-receptor agonist, for reducing IOP and treating glaucoma. Cell viability in the presence of 1A was measured using [3-(4, 5-dimethyl-thiazol-2-yl) 2, 5-diphenyl-tetrazolium bromide] (MTT) assay in rabbit NPE ciliary non-pigmented and corneal epithelial cells, human retinoblastoma, and liver Huh7 cells. The effect of 1A on IOP was determined in acute glaucomatous rabbit hyaluronate model and phenol-induced chronic glaucomatous rabbit model. The origin of activity of 1A was investigated by generation of a homology model of hP2Y6-R and docking studies. 1A did not exert cytotoxic effects up to 100 mM vs. trusopt and timolol in MTT assay in ocular and liver cells. In normotensive rabbits, 100 μM 1A vs. xalatan, trusopt, and pilocarpine reduced IOP by 45 vs. 20–30%, respectively. In the phenol animal model, 1A (100 μM) showed reduction of IOP by 40 and 20%, following early and late administration, respectively. Docking results suggest that the high activity and selectivity of 1A is due to intramolecular interaction between Pα-BH3 and C5-OMe which positions 1A in a most favorable site inside the receptor. P2Y6-receptor agonist 1A effectively and safely reduces IOP in normotense, acute, and chronic glaucomatous rabbits, and hence may be suggested as a novel approach for the treatment of glaucoma.

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Abbreviations

IOP:

Intraocular pressure

MTT:

[3-(4, 5-dimethyl-thiazol-2-yl) 2,5-diphenyl-tetrazolium bromide]

UDP:

Uridine 5′-diphosphate

hP2Y6-R:

Human P2Y6 receptor

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Acknowledgements

The authors gratefully acknowledge the support of the Office of the Israeli Chief Scientist, and Youdim Pharmaceuticals Ltd. Israel.

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Authors and Affiliations

  1. GlaucoPharm Ltd, P.O.Box 620, New Industrial Park, 20692, Yokneam, Israel

    Tali Fishman Jacob, Moussa B. H. Youdim & Orly Weinreb

  2. Department of Chemistry, Gonda-Goldschmied Medical Research Center, Bar-Ilan University, 52900, Ramat Gan, Israel

    Vijay Singh, Mudit Dixit, Tamar Ginsburg-Shmuel, Dan T. Major & Bilha Fischer

  3. Escuela Universitaria De Optica, Universidad Complutense De Madrid, C/Arcos De Jalon 118, 28037, Madrid, Spain

    Begoña Fonseca & Jesus Pintor

Authors
  1. Tali Fishman Jacob
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  2. Vijay Singh
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  3. Mudit Dixit
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  4. Tamar Ginsburg-Shmuel
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  5. Begoña Fonseca
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  6. Jesus Pintor
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  7. Moussa B. H. Youdim
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  8. Dan T. Major
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  9. Orly Weinreb
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  10. Bilha Fischer
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Corresponding authors

Correspondence to Dan T. Major, Orly Weinreb or Bilha Fischer.

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Conflict of interest

Authors Orly Weinreb and Tali Fishman-Jacob received research grants from the Office of the Israeli Chief Scientist, and Youdim Pharmaceuticals Ltd. Israel.

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This study does not contain any studies with human participants.

Additional information

₤ Patent—US Application No. 61/344,972 of 01/12/2010 and US Application No. 61/467,108 of 24/03/2011 International Filing: e:01/12/2011

Electronic supplementary material

ESM 1

Supporting Information includes: Homology modeling description; binding-site description and ligand recognition mode; binding interactions of hP2Y6-R and agonists; uracil moiety binding mode; and binding modes of 5-OMe-UDP(α-B) diastereoisomers. 3 Tables and 11 Figures are submitted as part of the Supporting Information. (DOCX 31124 kb)

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Jacob, T.F., Singh, V., Dixit, M. et al. A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist. Purinergic Signalling 14, 271–284 (2018). https://doi.org/10.1007/s11302-018-9614-7

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