Exploring the Effect of Cyclization of Histamine H₁ 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 H₁ receptor (H₁R), a member of the family A G-protein coupled receptor. In this study, we show that the binding kinetics of H₁R antagonists at the H₁R is dependent on the cyclicity of both the aromatic head group and the amine moiety of H₁R ligands, the chemotypes that are characteristic for the first-generation H₁R antagonists. Fusing the two aromatic rings of H₁R ligands into one tricyclic aromatic head group prolongs the H₁R residence time for benchmark H₁R ligands as well as for tailored synthetic analogues. The effect of constraining the aromatic rings and the basic amines is systematically explored, leading to a coherent series and detailed discussions of structure-kinetics relationships. This study shows that cyclicity has a pronounced effect on the binding kinetics.