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J Biol Chem. 2014 Jul 25;289(30):21153-62. doi: 10.1074/jbc.M114.557629. Epub 2014 Jun 10.

Digoxin derivatives with enhanced selectivity for the α2 isoform of Na,K-ATPase: effects on intraocular pressure in rabbits.

Author information

1
From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel.
2
the Department of Ophthalmology, Asaf Harofeh Hospital, Zerifin 608183, Israel, and.
3
the Department of Ophthalmology, Kaplan Hospital, Rehovoth 76100, Israel.
4
From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel, Steven.Karlish@weizmann.ac.il.

Abstract

In the ciliary epithelium of the eye, the pigmented cells express the α1β1 isoform of Na,K-ATPase, whereas the non-pigmented cells express mainly the α2β3 isoform of Na,K-ATPase. In principle, a Na,K-ATPase inhibitor with selectivity for α2 could effectively reduce intraocular pressure with only minimal local and systemic toxicity. Such an inhibitor could be applied topically provided it was sufficiently permeable via the cornea. Previous experiments with recombinant human α1β1, α2β1, and α3β1 isoforms showed that the classical cardiac glycoside, digoxin, is partially α2-selective and also that the trisdigitoxose moiety is responsible for isoform selectivity. This led to a prediction that modification of the third digitoxose might increase α2 selectivity. A series of perhydro-1,4-oxazepine derivatives of digoxin have been synthesized by periodate oxidation and reductive amination using a variety of R-NH2 substituents. Several derivatives show enhanced selectivity for α2 over α1, close to 8-fold in the best case. Effects of topically applied cardiac glycosides on intraocular pressure in rabbits have been assessed by their ability to either prevent or reverse acute intraocular pressure increases induced by 4-aminopyridine or a selective agonist of the A3 adenosine receptor. Two relatively α2-selective digoxin derivatives efficiently normalize the ocular hypertension, by comparison with digoxin, digoxigenin, or ouabain. This observation is consistent with a major role of α2 in aqueous humor production and suggests that, potentially, α2-selective digoxin derivatives could be of interest as novel drugs for control of intraocular pressure.

KEYWORDS:

Digoxin Derivatives; Drug Design; Intraocular Pressure; Isoform Selectivity; Membrane Protein; Molecular Pharmacology; Na+/K+-ATPase; Protein Drug Interaction

PMID:
24917667
PMCID:
PMC4110318
DOI:
10.1074/jbc.M114.557629
[Indexed for MEDLINE]
Free PMC Article

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