Development of a pharmacophore model for histamine H-3 receptor antagonists, using the newly developed molecular modeling program SLATE

New molecular modeling tools were developed to construct a qualitative phar macophore model for histamine HQ receptor antagonists. The program SLATE su perposes ligands assuming optimum hydrogen bond geometry. One or two ligand s are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible Hg antagonists. In the derived mo del, four hydrogen-bonding site points and two hydrophobic pockets availabl e for binding antagonists are revealed. The model results in a better under standing of the structure-activity relationships of Ha antagonists. To vali date the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and th e two hydrophobic pockets simultaneously. These ligands have high HE recept or affinity, thereby illustrating how the model can be used in the design o f new classes of H-3 antagonists.