title: Interaction of progesterone derivatives with the digitalis target enzyme: impact of glycosidation on inhibitory potency.
abstract: As a function of the structural modification of the steroid nucleus, the inhibitory interaction of 11 progesterone derivatives with human Na/K-ATPase (Na+/K(+)-transporting ATPase, EC 3.6.1.37), through C3-O-rhamnosylation, is either much decreased or weakly up to strongly increased, so that the rhamnosyl residue contributes to the complementary Gibbs energy of interaction, at the most, the same Gibbs energy increment as realized in ouabain. After C3 beta-O-rhamnosylation, the activity of some progesterone derivatives considerably surpasses that of 3 beta-O-rhamnosyl-chlormadinolacetate, which has been known to elicit positive inotropy in cats. The progesterone derivatives (aglycons and glycosides), that have been analysed more closely, produce their effects by the same molecular mechanism of interaction with Na/K-ATPase as characteristic for digitalis aglycons and glycosides. The results promise to pave the way for the identification of the chemical nature of endogenous digitalis and for the design of novel inotropic drugs.
authors.affiliation: Academy of Sciences of GDR, Energy Conversion Unit, Central Institute of Molecular Biology, Berlin.
authors.forename: J
authors.initials: J
authors.lastname: Weiland
authors.forename: W
authors.initials: W
authors.lastname: Schönfeld
authors.forename: K H
authors.initials: KH
authors.lastname: Menke
authors.forename: K R
authors.initials: KR
authors.lastname: Repke
mesh_terms: D001711:Biotransformation; D002540:Cerebral Cortex / Q000201:enzymology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002715:Chlormadinone Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D004071:Digitalis Glycosides / Q000494:pharmacology*; D006027:Glycosides / Q000378:metabolism*; D006801:Humans; D009206:Myocardium / Q000201:enzymology; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004071:Digitalis Glycosides; D006027:Glycosides; D002715:Chlormadinone Acetate; C059236:chlormadinol acetate; D011374:Progesterone; D000254:Sodium-Potassium-Exchanging ATPase