title: Digoxin derivatives with enhanced selectivity for the α2 isoform of Na,K-ATPase: effects on intraocular pressure in rabbits.
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.
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel.
authors.forename: Adriana
authors.initials: A
authors.lastname: Katz
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Tal
authors.affiliation: the Department of Ophthalmology, Asaf Harofeh Hospital, Zerifin 608183, Israel, and.
authors.forename: Dan
authors.initials: D
authors.lastname: Heller
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Haviv
authors.affiliation: the Department of Ophthalmology, Kaplan Hospital, Rehovoth 76100, Israel.
authors.forename: Bilal
authors.initials: B
authors.lastname: Rabah
authors.affiliation: the Department of Ophthalmology, Asaf Harofeh Hospital, Zerifin 608183, Israel, and.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Barkana
authors.affiliation: the Department of Ophthalmology, Kaplan Hospital, Rehovoth 76100, Israel.
authors.forename: Arie L
authors.initials: AL
authors.lastname: Marcovich
authors.affiliation: From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel, Steven.Karlish@weizmann.ac.il.
authors.forename: Steven J D
authors.initials: SJ
authors.lastname: Karlish
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D004077:Digoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000378:metabolism; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000201:enzymology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011817:Rabbits; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D026902:Potassium Channel Blockers; D043684:Receptor, Adenosine A3; D004077:Digoxin; D015761:4-Aminopyridine; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Digoxin Derivatives; Drug Design; Intraocular Pressure; Isoform Selectivity; Membrane Protein; Molecular Pharmacology; Na+/K+-ATPase; Protein Drug Interaction