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

Purinergic Signalling
Tali Fishman JacobBilha Fischer

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-BH...Continue Reading

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Citations

Oct 30, 2020·Frontiers in Pharmacology·Anael Viana Pinto AlbertoLuiz Anastacio Alves
Dec 15, 2020·Biochemical Pharmacology·Ivar von Kügelgen
May 29, 2021·Bioorganic & Medicinal Chemistry Letters·Paola OlivaKenneth A Jacobson

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Software Mentioned

GraphPad Prism
Delphi
DMol3
DS
Discovery Studio ( DS )
Modeler
CDOCKER
Discovery Studio

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