Imidazolylpropylguanidines as histamine H2 receptor agonists: 3D-QSAR of a large series

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.