Structure-Activity Relationships of Agents Modifying Cholinergic Transmission

摘要

Structure activity relationship studies of hemicholinium (HC-3) analogs aredirected toward better understanding both the spatial aspect of the receptor interatomic distances between the 2 cationic heads. Several series of compounds including 4,4' biphenyl and trans/trans-cyclohexyl derivatives were investigated and both series were potent inhibitors of acetylcholine synthesis. One compound, N-methyl 4-methyl piperidine derivative in the biphenyl series, was a very active inhibitor of ACh synthesis. The unique tertiary amine analog was an active inhibitor of synthesis of acetylcholine. It is much less active than the quaternary derivative. We discovered that 4-hydroxy-piperidine analogs of hemicholinium have the same therapeutic index for protection of mice against paraoxon-induced toxicity as pyridostigmine. This was followed by the discovered of a whole family of very active anti-o-pagents. An acetal derivative is more effective and safer than pyridostigmine or physostigmine.