Cardiotonic agents. 3. A topographical model of the cardiac cAMP phosphodiesterase receptor

PW Erhardt, AA Hagedorn and M Sabio

Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.

Based on the pharmacophoric relationship heterocycle-phenyl-imidazole (H-P-I) and upon consideration of several potent inhibitors of cardiac cAMP phosphodiesterase, a topographical model of this receptor is proposed. The model consists of two binding sites which interact with H, two steric features, preferential rotation of P away from coplanarity with H, and a binding site for an electron-rich system (I). It is supported by molecular modeling studies and accommodates a variety of inhibitors. It also encompasses the active site of the enzyme and can distinguish cAMP from cGMP as substrates.

Volume 33, Issue 1, pp. 1-13, 01/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics