Digitalis structure-activity relationship analyses. Conclusions from indirect binding studies with cardiac (Na+ +...

Area of Science:

• Pharmacology
• Biochemistry
• Cardiovascular Research

Background:

• Cardiac (Na+ + K+)-ATPase is a key target for cardiotonic steroids.
• Structure-activity relationships (SAR) of these steroids are crucial for understanding their effects.

Purpose of the Study:

• To correlate the potencies of cardiotonic steroids with their binding affinities to cardiac (Na+ + K+)-ATPase.
• To investigate the pharmacological receptor for inotropy.

Main Methods:

• Direct and indirect binding studies using [3H]ouabain or [3H]digitoxin.
• Inhibition assays on beef and guinea pig cardiac (Na+ + K+)-ATPase.
• Comparison with positive inotropic potencies on guinea pig left atria.

Main Results:

• Strong correlations were found between binding affinities (KD values) and positive inotropic potencies.
• Similar relative potencies were observed for digitalis derivatives on both beef and guinea pig cardiac (Na+ + K+)-ATPase.
• Functional groups on steroids similarly influenced potency in both inotropy and ATPase binding studies.

Conclusions:

• The pharmacological receptor for inotropy is part of the cardiac (Na+ + K+)-ATPase enzyme.
• [3H]ouabain or [3H]digitoxin binding inhibition effectively determines digitalis derivative potencies.
• The binding site for digitalis derivatives is similar across species, and SAR studies are consistent for both inotropy and ATPase binding.