- The activity of a compound depends to a very great extent on the position of the
23-carbonyl oxygen, which is held quite rigidly by ring D and the double bond. The
standard is the position of the carbonyl relative to the rigid backbone of digitoxi-
genin. In synthetic analogs, every 0.22 nm deviation from this position causes a loss
of activity by one order of magnitude from a maximum IC 50 of 49 nM. This corre-
lation is highly significant, as the regression coefficient of r^2 =0.993 indicates. - Removal of the sugar portion allows epimerization of the 3β-OH group, with a
decrease in activity and an increase in toxicity due to changes in polarity.
More recently, a polypeptide of 49 amino acids was isolated from a sea anemone. This
compound, anthopleurine A (8.26), is 30 times more potent than the Digitalisglyco-
sides and is less toxic. The discovery stimulated speculation over the possibility of a
native inotropic peptide receptor, in a situation similar to the endorphin–opiate rela-
tionship, in which a plant alkaloid fortuitously fits a peptide receptor. Also an endoge-
nous digitalis-like activity was discovered in rat, guinea pig, and bovine heart
homogenates, which inhibited Na+–K+–ATPase and had an affinity for the steroid recep-
tor one to two orders of magnitude higher than digoxin. This cardiodigin may be the
long-sought endogenous cardioactive factor.
8.2.3.3 Miscellaneous ATPase Drugs
The H+–K+–ATPase acts as the proton pump in the parietal cells of the stomach mucosa.
It transports protons and Cl−ions into the stomach via a K+antiport. Substituted benz-
imidazoles, such as omeprazole (8.27) inhibit this enzyme and are 2–12 times as active
as cimetidine (8.28) in inhibiting gastric stimulation.
8.2.4 Enzyme Targets: Carbonic AnhydraseCarbonic anhydrase (E.C. 4.2.1.1) is an enzyme located in the renal tubular epithelium
and in red blood cells. It catalyzes the seemingly simple reaction
H 2 O+CO 2 →H 2 CO 3 →HCO 3 −+H 3 O+which would be shifted far to the left without an enzyme.
494 MEDICINAL CHEMISTRY