Synthesis of quaternary ammonium salts of tricyclic cationic drugs as tools for investigating drug‐membrane interactions

The exact mechanism(s) by which tricyclic cationic drugs elicit their pharmacological effects is incompletely understood. Evidence exists that suggests that one important component of drug‐membrane interaction may involve electrostatic interactions with the anionic lipids that are enriched in the inner leaflet of cellular membranes, a hypothesis consistent with the ability of such drugs to induce stomatocytosis in erythrocytes. In the course of our studies experiments were planned that required the synthesis of quaternary ammonium derivatives of several drugs. Although the synthesis of such methylated derivatives has been described, these protocols often result in the formation of a variety of unwanted side products. In the present work, a rapid technique for the methylation of chlorpromazine and imipramine is demonstrated by reaction with substoichiometric amounts of methyl iodide followed by removal of unreacted parent drug by simple solvent wash. The technique described consistently yields pure product as evidenced by a variety of analytical techniques as well as an alteration in the ability of the drug to induce specific morphological changes in erythrocytes. This work was supported by a grant from the Howard Hughes Medical Institute, an NSF‐REU grant, and an IBM Faculty Research Grant from Santa Clara University.