Synthesis of 20-hydroxy-, 20-amino-, and 20-nitro-14-hydroxy-21-nor-5 beta,14 beta-pregnane C-3 glycosides and related derivatives: structure-activity relationships of pregnanes that bind to the digitalis receptor.
The preparation of derivatives of 14-hydroxy-21-nor-5 beta,14 beta-pregnane and 5 beta,14 beta-pregnane C-3 alpha-L-rhamnosides and tris-beta-D-digitoxosides is described. These derivatives, possessing a C-17 beta COCH2OH, CH2OH, CO2H, CO2Me, CH2NH2, or CH2NO2 group, bind to the digitalis receptor recognition site of heart muscle as measured in a radioligand binding assay. The 21-norpregnane derivatives consistently show greater binding affinity than the corresponding 20 alpha- and 20 beta-pregnane analogs. The C-20 nitro rhamnoside is comparable to digitoxin in binding affinity. The 17 beta-CH2NO2 group is the most effective replacement for the unsaturated lactone in the binding assay found so far, showing binding affinity comparable to that of the cardiac glycosides.
Templeton
J F
JF
Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada.
Ling
Y
Y
Zeglam
T H
TH
LaBella
F S
FS
D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D002316:Cardiotonic Agents / Q000138:chemical synthesis*; D006027:Glycosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011278:Pregnanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011955:Receptors, Drug / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D006027:Glycosides; D011278:Pregnanes; D011955:Receptors, Drug; C027082:digitalis receptor; D000254:Sodium-Potassium-Exchanging ATPase