Theoretical studies on the histamine H2 receptor: molecular mechanism of action of antagonists.

The previously defined sites in the histamine H2 receptor model [Mol. Pharmacol. 40:980-987 (1991)] were used to elucidate the pharmacological mechanism of action of compounds that act as antagonists at the receptor. In this model, a formate anion is used both as the negative site at which the histamine cation is anchored to the receptor and as a proton acceptor site. An ammonium cation is used as a proton donor site. The proposed model of recognition of cimetidine, tiotidine, and ranitidine suggests that the monocationic form of the antagonists is the most favorable species to bind the receptor. Moreover, the mode of recognition follows the same trends obtained for compounds that act as agonists; the protonated site of the molecule, i.e., imidazolium in cimetidine, guanidinium in tiotidine, or substituted ammonium in ranitidine, anchors at the negative site of the receptor, whereas the nonbasic part, i.e., cyanoguanidine in cimetidine and tiotidine and nitrodiaminoethene in ranitidine, is located between the proton donor and acceptor sites. An energetic analysis of the interaction between the antagonists and the receptor model, including the energies of ligand desolvation, shows that histamine cannot compete effectively with cimetidine, tiotidine, or ranitidine for binding to the H2 receptor. The predicted order of antagonist potencies, based on differences of formation enthalpies (delta delta H1), reproduces qualitatively the experimental rank order.