ISSN:
1432-1912
Keywords:
Na+/K+-transporting ATPase
;
Cardioactive steroids
;
Structure-activity relationship
;
Extrathermodynamic approach
;
Lead structure
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary 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 K i value equaled the apparent K D value, K′D was expressed in terms of the apparent standard Gibbs energy change ΔGo′ 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. 1. Cassaine, canrenone, prednisolone- and progesterone-3,20-bisguanylhydrazone, and chlormadinol acetate are compounds that are not congeneric with digitalis. 2. The butenolide ring of cardenolides or the analogous side-chains at C17β of 5β,14β-androstane-3β,14-diol are not pharmacophoric substructures, but merely amplifiers of the interaction energy of the steroid lead. 3. 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. 4. 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. 5β,14β-androstane-3β,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 C17β and the sugar substituent at C3β-OH to the overall interaction energy, i.e. this steroid nucleus is the lead structure. 6. The tridigitoxose side-chain at C3β-OH of digitalis glycosides can be more than isoenergetically replaced by glucose, 2′,3′-O-isopropylidene-rhamnose, digitoxose, rhamnose and 4′-deoxy-4′-amino-rhamnose (increasing order of interaction energy increments) indicating a remarkable degree of conformational adaptability of the sugar binding subsite.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00496377
Permalink
