Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure.
The ciliary epithelium in the eye consists of pigmented epithelial cells that express the α1β1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the α2β3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for α2β3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R-NH2 substituents and identified derivatives with significant selectivity for human α2β1 over α1β1 (up to 7.5-fold). When applied topically, the most α2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the β1 subunit, Gln84, suggesting a role for β in digoxin binding. Gln84 in β1 is replaced by Val88 in β3. Assuming that alkyl substituents might interact with β3Val88, we synthesized perhydro-1,4-oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for α2β3 over α1β1 (22-33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that α2β3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy.
Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel;
Adriana
A
Katz
Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel;
Daniel M
DM
Tal
Department of Ophthalmology, Asaf Harofeh Hospital, Zerifin 70300, Israel;
Dan
D
Heller
Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel;
Michael
M
Habeck
Israel National Centre for Personalized Medicine, Weizmann Institute of Science, Rehovoth 76100, Israel;
Efrat
E
Ben Zeev
Department of Ophthalmology, Kaplan Hospital, Rehovoth 76293, Israel.
Bilal
B
Rabah
Department of Ophthalmology, Asaf Harofeh Hospital, Zerifin 70300, Israel;
Yaniv
Y
Bar Kana
Department of Ophthalmology, Kaplan Hospital, Rehovoth 76293, Israel.
Arie L
AL
Marcovich
Department of Biological Chemistry, Weizmann Institute of Science, Rehovoth 76100, Israel; Steven.Karlish@weizmann.ac.il.
Steven J D
SJ
Karlish
D000818:Animals; D002417:Cattle; D004077:Digoxin / Q000494:pharmacology*; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D007527:Isoenzymes; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase
Na/K-ATPase; digoxin derivatives; intraocular pressure; α2β3 isoform