QSAR and Molecular Modelling Studies on Histamine H1‐Receptor Antagonists

Abstract

AbstractIn this review article all relevant QSAR and molecular modelling studies that have been performed on both classical and non‐classical histamine H1‐antagonists are evaluated. Comparison of the results from these studies gives more insight into the physico‐chemical and conformational features that define receptor binding of H1‐antagonists. QSAR analyses indicate that at least seven classes of classical H1‐antagonists bind at the same receptor site. For these compounds a basic amino‐group, an aromatic ring (the so‐called “cis”‐ring) and a hydrophobic group (at the position of the so‐called “trans”‐ring) are essential for receptor binding. Similarities in the QSAR equations of diphenhydramines, mono‐phenyl analogues of diphenhydramines and benzimidazoles show that hydrophobic and steric factors are important for binding at the “trans”‐ring location. In literature it has been suggested that both aromatic rings of the non‐classical OPPI compounds can be superimposed in a folded conformation on the “cis”‐ and “trans”‐ring of the classical H1‐antagonist model. Although this idea remains interesting, QSAR data indicate that the proposed superimposition is probably not valid.Most molecular modelling studies performed on H1‐antagonists appear to have major draw‐backs: (1) e.g. only crystal structures were studied andor (2) antagonists were superimposed on the agonist histamine, whereas no experimental evidence is available that agonists and antagonists occupy similar receptor sites and/or (3) not all low energy conformations were considered. The most important conclusion that can be drawn from these modelling studies is that the optimal distance between the basic nitrogen atom and one of the aromatic rings is around 6 Å. Furthermore, two models of the H1‐antagonist binding site based on superimposition of antagonists on the classical semi‐rigid compound cyproheptadine are compared. It is concluded that cyproheptadine with the piperidylene ring in a boat conformation can be be used as a template for further modelling studies.