AN INTERACTION-MODEL FOR TIOTIDINE AND ANALOGS WITH THE HISTAMINE-H2-RECEPTOR

For studying the interaction of compounds with a receptor it is important to have a pharmacophoric model which describes the possible sites of interaction. The high flexibility of H-2-antagonists such as cimetidine, ranitidine and tiotidine hampered the definition of such a 3D interaction model for the H-2-receptor. However, for tiotidine a number of analogues are known which do not only have different substituents at various parts of the molecule, but which are rigid as well. This makes these compounds suitable for the purpose of defining a pharmacophoric model. Based upon a comparison of the various tiotidine analogues it was possible to determine four sites of interaction. Two receptor binding sites interact with the two NH2 groups present in the 2-guanidine group of tiotidine. The third site at the receptor interacts with the NH2 group of the cyanoguanidine moiety which is connected to the ethylthiomethyl chain; this NH2 group functions as a proton donor. The fourth binding site was found via a tiotidine analogue in which the flexible side chain had been replaced by a 4(5) imidazole group. One of the nitrogens of this imidazole ring functions as a proton donor. The orientation of this proton donor parallels the orientation of the proton donor function present in the cyanoguanidine group of tiotidine itself, leading to the suggestion that these two proton donor functions interact with the same receptor site. The results from these structural considerations, are summarized in a schematic model that can be used for subsequent studies on different groups of H-2-antagonists.