Rosamaria Micheletti

Are the imidazoles of cimetidine and mifentidine bioisostere

Abstract Studies on protonation of the amidino group present in mifentidine have shown that this H2-receptor antagonist exists predominantly as a formamidinium monocation (95.3%) at physiological pH. Further studies on the preferred conformation by quantum mechanics and molecular mechanics methods have led us to formulate the hypothesis that the active population at the H2-receptor is the monoprotonated form. In order to answer the question, whether the imidazole in mifentidine plays the same role as that present in cimetidine, a number of bioisosteric replacements of this moiety have been performed on the two prototype molecules and their effects tested comparatively in in vitro functional and ligand-binding studies. The results of the study allow the conclusion to be drawn that the role played by the imidazole of mifentidine in blocking the H2-receptor is different from that played by the same group in cimetidine.