Quantum Chemical Studies of H2‐Antagonist‐Receptor Complexes. Cimetidine and Related Compounds

Abstract

AbstractMolecular and conformational properties of H2‐receptor antagonists were studied by means of the semiempirical MNDO (Modified Neglect of Differential Overlap) approximation. The compounds investigated were cimetidine (N″‐cyano‐N‐methyl‐N′‐[2‐[(5‐methylimidazol‐4‐yl methyl)thio]ethyl]guanidine) analogues, in which the cyanoguanidine moiety was replaced by various other neutral dipolar groups. A strong relation was found between, H2‐antagonistic activity as measured in vitro on the histamine stimulated guinea pig right atrium, one of the components of the overall MNDO dipole moment, and the lipophilic character of the different substituent groups. The dipole moment component points along the direction of the amidine N′H‐bond suggesting the relevance of hydrogen bond formation upon binding of the ligand to the H2‐receptor molecule. This theoretical study demonstrates that the semiempirical quantum chemical MNDO method might be helpful in calculating molecular properties as e.g. dipole moments, both in cases were experimental data are lacking, and in cases where experimental data are obtained under conditions which deviate strongly from the situation in which the ligand most probably is present when bound to the receptor macromolecule. An incorrect use of quantum chemical properties is discussed.