科研之友
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摘要
In the ciliary epithelium of the eye, the pigmented cells express the alpha 1 beta 1 isoform of Na, K-ATPase, whereas the nonpigmented cells express mainly the alpha 2 beta 3 isoform of Na, K-ATPase. In principle, a Na, K-ATPase inhibitor with selectivity for alpha 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 alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 isoforms showed that the classical cardiac glycoside, digoxin, is partially alpha 2-selective and also that the tris-digitoxose moiety is responsible for isoform selectivity. This led to a prediction that modification of the third digitoxose might increase alpha 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 alpha 2 over alpha 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 alpha 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 alpha 2 in aqueous humor production and suggests that, potentially, alpha 2-selective digoxin derivatives could be of interest as novel drugs for control of intraocular pressure.
- 出版日期2014-7-25
