Biological evaluation of some biphenyl analogs of acetyl-seco-hemicholinium No. 3.

The oxygen atoms in the esteratic moiety of acetyl-seco-hemicholinium No. 3 (AcHC-3) were replaced with carbon to form the ether, ketone and aliphatic analogs. Also, the thio and acetylthio-seco analogs of hemicholinium No. 3 (HC-3) were studied. When evaluated in the rabbit sciatic nerve-gastrocnemius muscular preparation all of the analogs caused neuromuscular blockades in two or three separate phases. The first phase of blockade caused by the ketone and thio analogs was rapid in onset and reversed by neostigmine. It was presumably competitive in type. The first phase of blockade caused by the ether and aliphatic analogs was increased by neostigmine and was concluded to be of the non-competitive type. All analogs caused a second phase of blockade that was reversed by choline and is typical of HC-3. A third blockade was found following the ether and ketone analogs. All of the analogs were more active as inhibitors of the true and pseudocholinesterases than was HC-3. All of the analogs were much less potent as inhibitors of acetylcholine synthesis than was AcHC-3. The implications of these findings are discussed.