Digoxin derivatives with enhanced selectivity for the ?2 isoform of Na,K-ATPase: effects on intraocular pressure in rabbits.

ABSTRACT: In the ciliary epithelium of the eye, the pigmented cells express the ?1?1 isoform of Na,K-ATPase, whereas the non-pigmented cells express mainly the ?2?3 isoform of Na,K-ATPase. In principle, a Na,K-ATPase inhibitor with selectivity for ?2 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 ?1?1, ?2?1, and ?3?1 isoforms showed that the classical cardiac glycoside, digoxin, is partially ?2-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 ?2 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 ?2 over ?1, 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 ?2-selective digoxin derivatives efficiently normalize the ocular hypertension, by comparison with digoxin, digoxigenin, or ouabain. This observation is consistent with a major role of ?2 in aqueous humor production and suggests that, potentially, ?2-selective digoxin derivatives could be of interest as novel drugs for control of intraocular pressure.

SUBMITTER: Katz A 

PROVIDER: S-EPMC4110318 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature