The lead structure in cardiac glycosides is 5 ?,14 ?-androstane-3 ?,14-diol

Abstract

The purpose of the present study was to determine the lead structure in cardiac glycosides at the receptor level, i.e. the minimal structural requirement for specific and powerful receptor recognition. Accordingly 73 digitalis-like acting steroids were characterized as to the concentration effecting half-maximum inhibition of Na,K-ATPase from human cardiac muscle under standardized turnover conditions. Since the Ki value equaled the apparent KD value, K'D was expressed in terms of the apparent standard Gibbs energy change delta G degrees' of steroid interaction with Na,K-ATPase. This allowed the use of the extrathermodynamic approach as a rational way of correlating in a quantitative manner, the potency and structure of the various steroidal compounds. The results of the present analysis taken in conjunction with relevant findings reported in the literature, favour the following conclusions. Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis. The butenolide ring of cardenolides or the analogous side-chains at C17 beta of 5 beta, 14 beta-androstane-3 beta, 14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead. All modifications of the structure, geometry and spatial relationship between the steroid nucleus and butenolide side chain of digitoxigenin all at once weaken the close fit interaction with the steroid and butenolide binding subsites of the enzyme in such way that the cardenolide derivatives interact with the receptor binding site area in whatever orientation that will minimize the Gibbs energy of the steroid-receptor-solvent system. The "butenolide carbonyl oxygen distance model" (Ahmed et al. 1983) for the interpretation of the differences in potency of the cardenolide derivatives describes the change in interaction energy through structural modification as a function of the entire molecule. 5 beta, 14 beta-androstane-3 beta, 14-diol, the steroid nucleus of cardiac glycosides of the digitalis type, is the minimum structure for specific receptor recognition and the key structure for inducing protein conformational change and thus Na,K-ATPase inhibition. It is also the structural requirement for maximum contributions of the butenolide substituent at C17 beta and the sugar substituent at C3 beta-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure.(ABSTRACT TRUNCATED AT 400 WORDS)

Crystal structure of the sodium-potassium pump (Na + ,K + -ATPase) with bound potassium and ouabain

“…3C), likely contributing to high affinity binding. This feature agrees well with the observation that the NH 2 substitution of the hydroxyl at C4* provides the highest affinity (25), because it will form a hydrogen bond with Glu-122 as well as Glu-319 (Fig. 3C), a residue affecting ouabain binding (8).…”

Structure-Activity Relationships for the Hypertensinogenic Activity of Ouabain

“…The response of the latter enzymes to the analogs used is not known. However, studies of the structureactivity relationships for inhibition of Na,K-ATPase by large numbers of cardiotonic steroids 15,16,30 suggest that a similar macroscopic pattern applies generally across different species and tissues in spite of large differences in affinities. Therefore, the rank order pattern for the OUA analogs observed with the dog enzyme is likely to apply, at least in a broad way, to each of the rat isoforms.…”

“…14 Because ouabain and digoxin have comparable potency as inhibitors of the isoforms of the rat sodium pump, 15 we suspected that the long-term pressor activity of ouabain might be independent of its ability to inhibit the sodium pump (Na,K-ATPase). Because the sugar and integrity of the lactone ring have quantitative contributions to the high potency of ouabain as an inhibitor of Na,K-ATPase, 16 we investigated a series of natural and synthetic analogs of ouabain for their effects on long-term blood pressure in normal rats. In each analog, the integrity of the steroid nucleus was maintained so the hemo-dynamic impact of structural alterations that affect their potency as inhibitors of Na,K-ATPase could be determined.…”

Active ingredients in Chinese medicines promoting blood circulation as Na+/K+-ATPase inhibitors

“…While they show considerable structural diversity, all members of this family share a common steroidal framework, regarded as the pharmacophoric moiety responsible for the activity of these compounds [27] . Generally, this steroid core is double-substituted with an unsaturated lactone ring at position 17 and a sugar portion at position 3; and this lactone moiety of cardiac glycosides is critical for their potent inhibition of Na + /K + -ATPase.…”