Imidazolylpropylguanidines as histamine H_2 receptor agonists: 3D-QSAR of a large series

Abstract

Imidazolylpropylguanidines are potent histamine H2 receptor agonists and act as inotropic vasodilators. A large series of 141 derivatives was tested in the isolated guinea pig atrium and submitted to CoMFA. Since all compounds are full agonists, pD2 values reflect H2 receptor binding. Hydrophobicity was considered as Σf of the variable structural moiety, calculated by the Leo–Hansch method. Preliminary Hansch analysis with Σf, (Σf)2 and indicator variables showed that pD2 additively depends on contributions of certain substructures and has a hydrophobic optimum. For CoMFA, all 3D structures were optimized and aligned. Partial Least Squares analysis of pD2 as function of steric and electrostatic field variables and of Σf and (Σf)2 led to models with r2 of 0.78 with and 0.93 without hydrophobicity. Results indicate a parabolic dependence of pD2 on hydrophobic effects. The 3D distribution of field influences on pD2 suggests a model (shape and electrostatic potential) of the binding site. The role of branching and different substituent effects of a first and a second ring indicate that adequately branched structures induce a conformational change of the binding site enabling a favourable accommodation of the second ring with various substituents.