3D‐QSAR CoMFA Study to Predict Orientation of Suprahistaprodifens and Phenoprodifens in the Binding‐Pocket of Four Histamine H 1 ‐Receptor Species

Several phenylhistamines and histaprodifens were identified to act as (partial) agonists at the histamine H 1 ‐receptor (H 1 R). The large diversity of these compounds led to p K i values in a range between 4.5–7.5 at human, rat, bovine and guinea‐pig histamine H 1 R. Hybrid molecules, consisting of two different H 1 R‐agonist partial structures, like suprahistaprodifens or phenoprodifens for example, or compounds with a dimeric histamine moiety are able to bind in two different orientations into the binding‐pocket of the H 1 R. In order to predict the percentage of ligand bound in orientation 1 or in orientation 2, 3D‐QSAR studies at four H 1 R species were performed. The training set contains ligands which can only bind in one orientation and the test set all ligands with two possible orientations. In general, the predicted p K i values of the test compounds were in good correlation to the experimental ones. Additionally, the predicted p K i values for all ligands with two possible orientations were used to calculate the percentage of the hybrid ligands bound in orientation 1 and 2. Our models suggest that the preferred orientation of these hybrid molecules is dependent on ligand and H 1 R species.