Origin of differences of inhibitory potency of cardiac glycosides in Na+/K+-transporting ATPase from human cardiac muscle, human brain cortex and guinea-pig cardiac muscle

Schönfeld, Werner; Schönfeld, Reinhild; Menke, Karl-Heinz; Weiland, Jürgen; Repke, K.

doi:10.1016/0006-2952(86)90416-8

Cited by 46 publications

(14 citation statements)

References 35 publications

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“…Our results confirm previous reports that alkylation of the lactone ring clearly decreases the cardiac steroid-induced inhibition of the Na + /K + -ATPase (Schönfeld et al 1985(Schönfeld et al , 1986Staroske et al 1996). Thus the allyl derivative C discussed in the present paper has a low K′ D (4 × 10 -5 M).…”

Section: Structure-activity Relationshipssupporting

confidence: 81%

“…B is almost as active as digitoxigenin. The corresponding 3-acetate is somewhat less potent in human enzyme preparations (Schönfeld et al 1986). It is very informative to compare the activity of B with that of the 22-(2-oxopropyl) analogue which differs from B only by the fact that the oxygen at C-22 is replaced by a CH 2 group.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

See 1 more Smart Citation

Na+/K+ pump inhibition and positive inotropic effect of digitoxigenin and some C-22-substituted derivatives in sheep cardiac preparations

Erlenkamp

Gretzer

Zillikens

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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Affinity labeling might be used to localize the binding site(s) of the lactone ring of cardioactive steroids on the Na+/K+-ATPase. The aim of the experiments described below was to identify C-22-substituted derivatives of digitoxigenin suitable for this purpose. The positive inotropic effect of digitoxigenin, 22-benzoyloxy-digitoxigenin, 22-acetoxy-digitoxigenin, 22-allyl-digitoxigenin, and 22-hydroxy-digitoxigenin was studied in sheep cardiac Purkinje fibres. In addition, the inhibition of the Na+/K+ pump by these drugs was investigated by means of simultaneous measurements of membrane current and intracellular Na+ concentration in voltage-clamped Purkinje fibres and by means of whole-cell recording in isolated sheep Purkinje cells. The experiments were performed at 5.4 mM K+ and 30 to 33 degrees C. All compounds exerted a reversible positive inotropic effect. The concentrations required for the half maximal effect (EC50 value) amounted to approximately 5 x 10(-7) M digitoxigenin, 22-acetoxy-digitoxigenin or 22-hydroxy-digitoxigenin. The EC50 values for 22-benzoyloxy-digitoxigenin and 22-allyl-digitoxigenin were estimated to be 1.3 x 10(-6) M and 1.1 x 10(-5) M, respectively. From measurements on voltage-clamped Purkinje fibres the concentrations required for half maximal Na+/K+ pump inhibition (K'D value) were calculated to be approximately 10(-6) M for digitoxigenin, 22-acetoxy-digitoxigenin or 22-hydroxy-digitoxigenin. The K'D value for 22-benzoyloxy-digitoxigenin was 10 times larger. The K'D value for 22-allyl-digitoxigenin was even larger and amounted to approximately 4 x 10(-5) M. The K'D values of the drugs derived from whole-cell recording on single Purkinje cells tended to be smaller by a factor 2 to 8. Measurements of drug binding and unbinding revealed that the apparent association rate constant of 22-benzoyloxy-digitoxigenin (approximately 9 x 10(2) s(-1) M[-1]) was smaller than the association rate constant of digitoxigenin (approximately 2 x 10(4) s(-1) M[-1]), whereas the apparent dissociation rate constants of both compounds were similar (approximately 4 x 10(-3) s[-1]). Compared to digitoxigenin 22-allyl-digitoxigenin displayed a lower association rate constant (approximately 3 x 10(3) s(-1) M[-1]) and a larger dissociation rate constant (approximately 8 x 10(-2) M[-1]). The structure-activity relationships of the drugs are discussed. We conclude that esters derived from 22-hydroxy-digitoxigenin might be suitable to localize the binding site(s) of the lactone moiety on the Na+/K+ pump by affinity labeling.

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Section: Structure-activity Relationshipssupporting

confidence: 81%

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Na+/K+ pump inhibition and positive inotropic effect of digitoxigenin and some C-22-substituted derivatives in sheep cardiac preparations

Erlenkamp

Gretzer

Zillikens

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…a strong ionic interaction between one of carboxylate residues present in the α-subunit of the Na + ,K + -ATPase and the cationic form of some digitalis like derivatives is relevant for interference with enzyme activity [55, 87]. The presence of -OH groups at different positions of the steroidal skeleton (Figure 1) reduces, in general, the interaction energy, though it depends on the location and spatial disposition of such –OH groups [88, 89]. …”

Section: Inhibition Of Na+k+-atpase Activitymentioning

confidence: 99%

Na+,K+-ATPase as the Target Enzyme for Organic and Inorganic Compounds

Vasić

Momić

Petković

et al. 2008

Sensors

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This paper gives an overview of the literature data concerning specific and non specific inhibitors of Na+,K+-ATPase receptor. The immobilization approaches developed to improve the rather low time and temperature stability of Na+,K+-ATPase, as well to preserve the enzyme properties were overviewed. The functional immobilization of Na+,K+-ATPase receptor as the target, with preservation of the full functional protein activity and access of various substances to an optimum number of binding sites under controlled conditions in the combination with high sensitive technology for the detection of enzyme activity is the basis for application of this enzyme in medical, pharmaceutical and environmental research.

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“…Any change on that spatial disposition, modifying A and/or B rings related to B-C plane, decreases the interaction energy [48]. This can be observed in the case of variation of the configuration 5β to 5α or introduction of a ∆ 5 double bond, even when such a decrease is not very high.…”

Section: Steroidal Frameworkmentioning

confidence: 88%