RT Journal Article
T1 A promising drug candidate for the treatment of glaucoma based on a P2Y6-receptor agonist
A1 Jacob, Tali Fishman
A1 Singh, Vijay
A1 Dixit, Mudit
A1 Ginsburg-Shmuel, Tamar
A1 Fonseca Vázquez, Begoña
A1 Pintor Just, Jesús Jerónimo
A1 Youdim, Moussa B. H.
A1 Major, Dan T.
A1 Weinreb, Orly
A1 Fischer, Bilha
AB 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.
PB Springer Verlag
SN 1573-9538
YR 2018
FD 2018-09
LK https://hdl.handle.net/20.500.14352/12993
UL https://hdl.handle.net/20.500.14352/12993
LA eng
NO 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, vol. 14, n.o 3, septiembre de 2018, pp. 271-84. DOI.org (Crossref), https://doi.org/10.1007/s11302-018-9614-7.
NO Electronic supplementary materialThe online version of this article ( https://doi.org/10.1007/s11302-018-9614-7) contains supplementary material, which is available to authorized users.
DS Docta Complutense
RD 17 abr 2025