A PHARMACOLOGIC EVALUATION OF HEMICHOLINIUM ANALOGS

¹ Department of Pharmacology, College of Medicine, University of Iowa, Iowa City, Iowa

The influence of structural modifications of 19 analogs of hemicholinium (HC-3) is discussed. The structural alterations in substitutions on the quaternary nitrogen result not only in marked quantitative differences in biologic properties but also in qualitative differences in pharmacologic activity. Hemicholinium- like activity was influenced markedly by modifying the position of the -hydroxyl groups as well as alkyl substitutions on the nitrogen. The -hydroxyl derivative and higher homologs of hemicholinium were relatively inactive when evaluated by various biologic tests. Substitution of a benzyl group for one of the methyl groups in hemicholinium resulted in a compound that, in addition to hemicholinium-like activity, was also a potent ganglionic blocking agent. Introduction of ,-dimethyl groups on the choline moiety produced a compound that, in addition to possessing hemicholinium-like activity, was also a potent curare-like neuromuscular blocking agent. It was demonstrated that hemicholinium- like inhibition of neuromuscular transmission could be produced by the heterocyclic analog, N-methylpiperidine. The -picoline derivative of hemicholinium was a potent inhibitor of acetylcholinesterase. Therefore, in this basic series of compounds, five separate pharmacologic properties could be demonstrated after structural alterations involving the catiomc head. Some of the problems in consideration of these biologically active compounds interacting with different receptors are discussed.