ON THE PROTONATION OF THE GUANIDINE ARM OF CIMETIDINE - A THEORETICAL-STUDY

The hypothesis that the activity of cimetidine, a member of a family o f anti-ulcer drugs, may depend on the protonation ability of the unsat urated nitrogens of its guanidine arm is studied quantitatively on the basis of energies and charge distributions determined by the PM3 meth od. At variance of histamine, whose two sites susceptible of proton ac tivity are more or less energetically equivalent, in cimetidine proton ation at the imidazole cycle is favoured. However, the ability of the cyano-guanidine arm to fur a proton depends on the conformation of the whole molecule and, in certain cases, it becomes comparable with that of the imidazole nitrogen. These points may provide a key to a better understanding of the mechanism of action of drugs of the cimetidine g roup.