ANTICHOLINESTERASE ACTIVITY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF A NEW SERIES OF HEMICHOLINIUM-3 ANALOGS

Piperidine derivatives of hemicholinium-3 were synthesized and included the following spacing groups between the bis-cationic heads: trans,trans-bicyclohexyl, phenanthrene, naphthalene and biphenyl. Anticholinesterase activity was determined using rat striatal synaptosomal cholinesterase, bovine erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase. Hemicholinium-3 has little anticholinesterase activity but when the choline moiety of hemicholinium-3 is replaced with selected heterocyclic amine ring systems active inhibitors can be obtained. Results in this communication identify several quaternary amines which are equipotent with physostigmine for inhibition of cholinesterase. Several tertiary amines were also found to be active. Optimal anticholinesterase activity of these piperidine derivatives appear to be related to the necessity of 14 .ANG. interatomic distance between the cationic heads as well as C=O substitution in the phenylethyl spacing moiety. Reduction of C=O to secondary alcohol or CH2 results in decreased activity. The anticholinesterase activity is not only related to internitrogen distance and C=O substitution but also structural planarity and positional isomerism of the quaternary cationic head.