Exploring the Effect of Cyclization of Histamine H Receptor Antagonists on Ligand Binding Kinetics.

There is an increasing interest in guiding hit optimization by considering the target binding kinetics of ligands. However, compared to conventional structure-activity relationships, structure-kinetics relationships have not been as thoroughly explored, even for well-studied archetypical drug targets such as the histamine H receptor (HR), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of HR antagonists at the HR is dependent on the cyclicity of both the aromatic head group and the amine moiety of HR ligands, the chemotypes that are characteristic for the first-generation HR antagonists.