4-(3'alpha15'beta-dihydroxy-5'beta-estran-17'beta-yl)furan-2-methyl alcohol: an anti-digoxin agent with a novel mechanism of action.
The synthesis and some pharmacological properties of 4-(3'alpha-15'beta-dihydroxy-5beta-estran-17'beta-yl)furan-2-methyl alcohol (16) have been described. The compound was synthesized by reacting a synthetic 3alpha- benzyloxy-5beta-estr-15-en-17-one with the ethylene acetal of 4-bromo-2-furancarboxyaldehyde, followed by hydrolysis of the ethylene acetal and reduction of the aldehyde. Despite its resemblance to the structure of cardiac steroids (CS), 16 does not bind to the CS receptor on Na(+),K(+)-ATPase and does not increase the force of contraction of heart muscle. However, 16 inhibited the digoxin-induced increase in the force of contraction and arrhythmias in guinea pig papillary muscle and human atrial appendages. The steroid also inhibited digoxin-induced alteration in endocytosed membrane traffic, indicating a novel mechanism of action.
Deutsch
Joseph
J
Department of Medicinal Chemistry, School of Pharmacy, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. odj@cc.huji.ac.il
Jang
Huang G
HG
Mansur
Nura
N
Ilovich
Ohad
O
Shpolansky
Uri
U
Galili
Dana
D
Feldman
Tomer
T
Rosen
Haim
H
Lichtstein
David
D
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004077:Digoxin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D004962:Estranes / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D011869:Radioligand Assay; D013574:Synaptosomes / Q000378:metabolism; D014168:Transferrin / Q000096:biosynthesis
C508796:4-(3',15'-dihydroxy-5'-estran-17'-yl)furan-2-methyl alcohol; D004962:Estranes; D014168:Transferrin; D004077:Digoxin